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Varicocele: Early Surgery versus Observation
Opposing Views
Varicocele: Early Surgery versus Observation OBSERVATION DECIDING on treatment for the fairly common (15% to 18%) asymptomatic idiopathic varicocele is a challenging problem in adolescent urology. Pediatric urologists are asked to predict the fertility future of boys who may not be attempting paternity for another decade or two. Despite numerous studies about varicocele evaluation and treatment, uncertainties remain. Overtreatment and under treatment are medically and financially costly. Expensive ultrasound, office visits and surgery must be avoided in those who do not need them, while early intervention is warranted in some to preempt the need for later assisted reproductive techniques. Although ultrasound measurements may be more accurate than using an orchidometer, this precision may not be needed. Differential testicular volume has traditionally been used as a marker for genital health in guiding the need for surgery, although without a clear cutoff consensus (10%, 15%, 20%). Recent evidence shows that total testicular volume is more predictive of total motile count than differential volume, although neither is as good as we would hope.1 The inability of a differential volume change to predict semen parameters (volume, density or motility) should raise questions about the true value of this parameter in varicocele management. While studies have proposed venous backflow as a predictor and an indication for surgery, its applicability can be hampered by the subjectivity of the procedure.2 Numerous studies confirm that ipsilateral testicular volume loss can be reversed after varicocele correction (partially caused by an increase in germ cell number and seminiferous tubule diameter) but surgical treatment should be considered cautiously as up to 71% of testicular volume disproportion can resolve spontaneously during adolescence.1 Moursy et al compared surgical versus nonsurgical management of unilateral varicoceles in adolescents.3 Catch-up testicular growth occurred in 70% and semen analysis became normal in all patients treated surgically, and catch-up growth occurred in 50% and semen analysis became normal
0022-5347/14/1923-0645/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
in all but 1 patient in the nonsurgical group. Importantly, testicular volume was no different between the groups. Bogaert et al suggested that there is no beneficial effect to screening for varicocele presence since treating the varicocele at diagnosis does not appear to improve later paternity.4 They evaluated the ability to achieve paternity in adults who had been diagnosed with a varicocele in adolescence and were either treated by antegrade sclerotherapy or received no further treatment. Some interval data were missing from this study, which may have helped us treat adolescents/young adults, including Tanner stage, testicular volume over time and semen analysis. Essentially though, the findings of Bogaert et al reinforce the historical data confirming that 80% to 85% of adults with varicocele are not having paternity issues prompting an infertility evaluation. In addition to the effect on germ cells, current research in adult varicocele indicates that a varicocele may affect testosterone levels. In a recent meta-analysis by Li et al mean serum testosterone levels increased by 97.5 ng/dl after surgical correction of the adult varicocele.5 Future research in this area is needed in pediatrics as testosterone levels can be a moving target throughout adolescence. Unfortunately, we have not yet found our perfect noninvasive yet cost-effective marker. In an attempt to decrease patient cost and optimize treatment, we have taken a standard approach at the Children’s Hospital of Philadelphia, beginning with yearly examination with an orchidometer (or every other year if normal total testicular volume) until the patient reaches Tanner 5 maturity. The patient is then offered a semen analysis and androgen hormone levels testing pituitary, Sertoli cell and Leydig cell function. If total testicular volume is low, semen parameters are low, androgen lab results are abnormal or if the patient is symptomatic (uncommon), we discuss surgical correction. If observation remains the treatment, then we encourage followup with an adult urologist until paternity is achieved.
http://dx.doi.org/10.1016/j.juro.2014.06.037 Vol. 192, 645-647, September 2014 Printed in U.S.A.
www.jurology.com
j
645
OPPOSING VIEWS
646
Currently, we are still left with the issue of identifying the worrisome varicocele outliers, which are 1) the boy with normal testicular volumes who will fall into the 15% to 20% group that will have difficulty achieving paternity as an adult and 2) the boy with low total testicular volume (or perhaps a large differential) who will not have a future paternity problem and should avoid surgical correction. It is still unclear whether the effects of the varicocele on the seminiferous tubules are absolutely irreversible or whether they will be reversed when the patient is a young adult. The fact that age at presentation was not predictive of any semen parameter analyzed by Christman et al argues against a progressive insult to spermatogenic potential caused by the adolescent varicocele.1 It seems that all patients with varicocele should be followed into adulthood if we are going to be able to determine the best parameters in adolescence that predict adult fertility. Only then will we really know whether we are making a difference in the overall testicular health of these patients. Thomas F. Kolon Department of Urology (Surgery) Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania
EARLY SURGERY The incidence of varicocele in adults and adolescents is similar at w15% and in as many as 20% it will be associated with a continuous decline in testicular histology and function, leading to abnormal semen parameters and infertility. By identifying those males with a varicocele who are destined for infertility early, even in adolescence, we may save them from future anguish. No one would advocate operating on all adolescents with a varicocele, but if we could designate those in whom fertility could be salvaged it would impact surgical decision making. The problem is we do not yet know how to perfectly identify this group. Kass and Belman alerted us to the fact that ipsilateral hypotrophy can occur in adolescent boys with a left varicocele and that hypotrophy could be reversed in 80% of them by varicocelectomy.6 Haans et al reported decreased total sperm counts in males with hypotrophy as young as 17 to 20 years.7 Subsequently, Cayan et al demonstrated that varicocelectomy improved low sperm concentration in 15 to 19-year-old males with hypotrophy, even in those who did not achieve catch-up growth.8 Finally, Diamond et al brought it together when they found that 11% of boys at Tanner stage 5 with 10% to 20% asymmetry and 53% with greater than 20%
asymmetry already had abnormal semen parameters, including most poignantly total sperm motility counts less than 10 million.9 However, while the focus has been on asymmetry, Christman et al found total testicular volume (TTV) to be the more significant measurement1 as did Kurtz et al in a subsequent study.10 In the latter study the authors noted that while low TTV had a significant relationship with low total sperm motility counts, the relationship between asymmetry and low total motile sperm levels was not significant despite the significance of that association in their prior study.9 However, when low TTV was associated with marked asymmetry, total motile sperm counts were at their lowest.10 In other words, low TTV, particularly when associated with increased ipsilateral asymmetry, should alert the physician not only to the possibility of abnormal sperm production, but also to the fact that the condition may be progressive. However, it is unclear what the normal range of TTV is for boys at each Tanner stage. What is important is to recognize that abnormal semen parameters may be much more reversible at younger ages than in grown men. While abnormal semen parameters may improve in as many as two-thirds of adults following left varicocelectomy, pregnancy rates unfortunately show significantly less improvement. There is an ongoing debate as to whether varicocelectomy actually does increase pregnancy rates in couples with infertility, with the most recent literature favoring varicocelectomy. Both studies that have tried to analyze the value of varicocelectomy in adolescence upon later pregnancy rates in adulthood suggest a benefit from early surgery.11,12 Pajovic and Radojeviv reported at least a 75% pregnancy rate in boys with varicoceles initially operated on between ages 15 and 19 years for abnormal semen parameters, a rate that evidently will become higher once more of this young group of men try to conceive.11 In the earlier study, Salzhauer et al reported a 100% pregnancy rate in 18 Hasidic/ultraorthodox men who were operated on in adolescence and in most cases asymmetry was greater than 10%.12 While Poon et al reported that 67% of those with greater than 15% asymmetry will have persistent or worse asymmetry after a median followup of 21 months,13 Kolon et al instead found that 74% will have catch-up growth to less than 15% asymmetry after a median followup of 39 months.14 As a result, they recommend waiting 3 years to determine if catch-up growth will occur spontaneously. More recently, they take a watch and wait approach toward adolescents, focusing more on TTV than asymmetry, and waiting until these boys reach age 18 years to offer semen analysis. Peak retrograde flow (PRF), asymmetry and TTV measurements obtained on Doppler ultrasound
OPPOSING VIEWS
can all be used to help identify those who need surgery, particularly in boys with earlier Tanner stage disease and in older boys for whom a semen analysis cannot be obtained. Paduch and Niedzielski reported on 17 to 19-year-old boys with grade II and III varicoceles, and noted poorer semen quality in those with greater backflow velocity and greater asymmetry.15 We now have reported in 3 series that the combination of a PRF 38 cm per second or greater and asymmetry 20% or greater, ie “the 20/38 harbinger,” almost uniformly portends persistent or worsening asymmetry. Van Batavia et al found that the “20/38 harbinger” can be extended to those with 15% asymmetry as well.16 While all ultrasonographers have experience measuring PRF in vessels elsewhere in the body, when studying veins of the spermatic cord, it is important that the PRF be obtained with the
647
patient supine and that a satisfactory Valsalva maneuver has been performed. In summary, we have been focused on the prevention of future infertility and prefer to operate with appropriate indications to prevent abnormal semen parameters from developing as opposed to operating in an attempt to reverse established abnormal parameters. We take into account PRF, asymmetry, TTV and testicular consistency when making our decisions. We support the use of semen analysis at ages 17 or 18 years in males who have not been operated on but in whom we still have a concern as to whether surgery should be performed. Kenneth I. Glassberg and Jason P. Van Batavia Department of Urology Columbia University Medical Center New York, New York
REFERENCES 1. Christman MS, Zderic SA, Canning DA et al: Active surveillance of the adolescent with varicocele: predicting semen outcomes from ultrasound. J Urol 2014; 191: 1401. 2. Kozakowski KA, Gjertson CK, Decastro GJ et al: Peak retrograde flow: a novel predictor of persistent, progressive and new onset asymmetry in adolescent varicocele. J Urol 2009; 181: 2717. 3. Moursy EE, ElDahshoury MZ, Hussein MM et al: Dilemma of adolescent varicocele: long-term outcome in patients managed surgically and in patients managed expectantly. J Ped Urol 2013; 9: 1018. 4. Bogaert G, Orye C and De Win G: Pubertal screening and treatment of varicocele do not improve future adult chance of paternity. J Urol 2013; 189: 2298. 5. Li F, Yue H, Yamaguchi K, Okada K et al: Effect of surgical repair on testosterone production in infertile men with varicocele: a meta-analysis. Int J Urol 2012; 19: 149.
6. Kass EJ and Belman AB: Reversal of testicular growth failure by varicocele ligation. J Urol 1987; 137: 475. 7. Haans LCF, Laven JSE, Mali WPTM et al: Testes volumes, semen quality, and hormonal patterns in adolescents with and without a varicocele. Fertil Steril 1991; 56: 731. 8. Cayan S, Akbay E, Bozlu M et al: The effect of varicocele repair on testicular volume in children and adolescents with varicocele. J Urol 2002; 168: 731. 9. Diamond DA, Zurakowski D, Bauer SB et al: Relationship of varicocele grade and testicular hypotrophy to semen parameters in adolescents. J Urol 2007; 178: 1584. 10. Kurtz MP, Rosoklija I, Johnson KL et al: Combined correlation of total testis volume and volume differential with total motile sperm counts in adolescent varicocele. Presented at the annual meeting of the Society for Pediatric Urology/ American Urological Association, Orlando, Florida, May 16-17, 2014.
11. Pajovic B and Radojeviv N: Prospective follow up of fertility after adolescent laparoscopic varicocelectomy. Eur Rev Med Pharmacol Sci 2013; 17: 1060. 12. Salzhauer EW, Sokol A and Glassberg KI: Paternity after adolescent varicocele repair. Pediatrics 2004; 114: 1631. 13. Poon SA, Cjertsen CK, Mercado MA et al: Testicular asymmetry in adolescent varicoceles managed expectantly. J Urol 2010; 183: 731. 14. Kolon TF, Clement MR, Cartwright L et al: Transient asynchronous testicular growth in adolescent males with a varicocele. J Urol 2008; 180: 111. 15. Paduch DA and Niedzielski J: Semen analysis in young men with varicocele: preliminary study. J Urol 1996; 156: 786. 16. Van Batavia JP, Badalato G, Fast A et al: Adolescent varicoceledis the 20/38 harbinger a durable predictor of testicular asymmetry? J Urol 2013; 189: 1897.
Varicocele: Early Surgery versus Observation OBSERVATION DECIDING on treatment for the fairly common (15% to 18%) asymptomatic idiopathic varicocele is a challenging problem in adolescent urology. Pediatric urologists are asked to predict the fertility future of boys who may not be attempting paternity for another decade or two. Despite numerous studies about varicocele evaluation and treatment, uncertainties remain. Overtreatment and under treatment are medically and financially costly. Expensive ultrasound, office visits and surgery must be avoided in those who do not need them, while early intervention is warranted in some to preempt the need for later assisted reproductive techniques. Although ultrasound measurements may be more accurate than using an orchidometer, this precision may not be needed. Differential testicular volume has traditionally been used as a marker for genital health in guiding the need for surgery, although without a clear cutoff consensus (10%, 15%, 20%). Recent evidence shows that total testicular volume is more predictive of total motile count than differential volume, although neither is as good as we would hope.1 The inability of a differential volume change to predict semen parameters (volume, density or motility) should raise questions about the true value of this parameter in varicocele management. While studies have proposed venous backflow as a predictor and an indication for surgery, its applicability can be hampered by the subjectivity of the procedure.2 Numerous studies confirm that ipsilateral testicular volume loss can be reversed after varicocele correction (partially caused by an increase in germ cell number and seminiferous tubule diameter) but surgical treatment should be considered cautiously as up to 71% of testicular volume disproportion can resolve spontaneously during adolescence.1 Moursy et al compared surgical versus nonsurgical management of unilateral varicoceles in adolescents.3 Catch-up testicular growth occurred in 70% and semen analysis became normal in all patients treated surgically, and catch-up growth occurred in 50% and semen analysis became normal
0022-5347/14/1923-0645/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
in all but 1 patient in the nonsurgical group. Importantly, testicular volume was no different between the groups. Bogaert et al suggested that there is no beneficial effect to screening for varicocele presence since treating the varicocele at diagnosis does not appear to improve later paternity.4 They evaluated the ability to achieve paternity in adults who had been diagnosed with a varicocele in adolescence and were either treated by antegrade sclerotherapy or received no further treatment. Some interval data were missing from this study, which may have helped us treat adolescents/young adults, including Tanner stage, testicular volume over time and semen analysis. Essentially though, the findings of Bogaert et al reinforce the historical data confirming that 80% to 85% of adults with varicocele are not having paternity issues prompting an infertility evaluation. In addition to the effect on germ cells, current research in adult varicocele indicates that a varicocele may affect testosterone levels. In a recent meta-analysis by Li et al mean serum testosterone levels increased by 97.5 ng/dl after surgical correction of the adult varicocele.5 Future research in this area is needed in pediatrics as testosterone levels can be a moving target throughout adolescence. Unfortunately, we have not yet found our perfect noninvasive yet cost-effective marker. In an attempt to decrease patient cost and optimize treatment, we have taken a standard approach at the Children’s Hospital of Philadelphia, beginning with yearly examination with an orchidometer (or every other year if normal total testicular volume) until the patient reaches Tanner 5 maturity. The patient is then offered a semen analysis and androgen hormone levels testing pituitary, Sertoli cell and Leydig cell function. If total testicular volume is low, semen parameters are low, androgen lab results are abnormal or if the patient is symptomatic (uncommon), we discuss surgical correction. If observation remains the treatment, then we encourage followup with an adult urologist until paternity is achieved.
http://dx.doi.org/10.1016/j.juro.2014.06.037 Vol. 192, 645-647, September 2014 Printed in U.S.A.
www.jurology.com
j
645
OPPOSING VIEWS
646
Currently, we are still left with the issue of identifying the worrisome varicocele outliers, which are 1) the boy with normal testicular volumes who will fall into the 15% to 20% group that will have difficulty achieving paternity as an adult and 2) the boy with low total testicular volume (or perhaps a large differential) who will not have a future paternity problem and should avoid surgical correction. It is still unclear whether the effects of the varicocele on the seminiferous tubules are absolutely irreversible or whether they will be reversed when the patient is a young adult. The fact that age at presentation was not predictive of any semen parameter analyzed by Christman et al argues against a progressive insult to spermatogenic potential caused by the adolescent varicocele.1 It seems that all patients with varicocele should be followed into adulthood if we are going to be able to determine the best parameters in adolescence that predict adult fertility. Only then will we really know whether we are making a difference in the overall testicular health of these patients. Thomas F. Kolon Department of Urology (Surgery) Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania
EARLY SURGERY The incidence of varicocele in adults and adolescents is similar at w15% and in as many as 20% it will be associated with a continuous decline in testicular histology and function, leading to abnormal semen parameters and infertility. By identifying those males with a varicocele who are destined for infertility early, even in adolescence, we may save them from future anguish. No one would advocate operating on all adolescents with a varicocele, but if we could designate those in whom fertility could be salvaged it would impact surgical decision making. The problem is we do not yet know how to perfectly identify this group. Kass and Belman alerted us to the fact that ipsilateral hypotrophy can occur in adolescent boys with a left varicocele and that hypotrophy could be reversed in 80% of them by varicocelectomy.6 Haans et al reported decreased total sperm counts in males with hypotrophy as young as 17 to 20 years.7 Subsequently, Cayan et al demonstrated that varicocelectomy improved low sperm concentration in 15 to 19-year-old males with hypotrophy, even in those who did not achieve catch-up growth.8 Finally, Diamond et al brought it together when they found that 11% of boys at Tanner stage 5 with 10% to 20% asymmetry and 53% with greater than 20%
asymmetry already had abnormal semen parameters, including most poignantly total sperm motility counts less than 10 million.9 However, while the focus has been on asymmetry, Christman et al found total testicular volume (TTV) to be the more significant measurement1 as did Kurtz et al in a subsequent study.10 In the latter study the authors noted that while low TTV had a significant relationship with low total sperm motility counts, the relationship between asymmetry and low total motile sperm levels was not significant despite the significance of that association in their prior study.9 However, when low TTV was associated with marked asymmetry, total motile sperm counts were at their lowest.10 In other words, low TTV, particularly when associated with increased ipsilateral asymmetry, should alert the physician not only to the possibility of abnormal sperm production, but also to the fact that the condition may be progressive. However, it is unclear what the normal range of TTV is for boys at each Tanner stage. What is important is to recognize that abnormal semen parameters may be much more reversible at younger ages than in grown men. While abnormal semen parameters may improve in as many as two-thirds of adults following left varicocelectomy, pregnancy rates unfortunately show significantly less improvement. There is an ongoing debate as to whether varicocelectomy actually does increase pregnancy rates in couples with infertility, with the most recent literature favoring varicocelectomy. Both studies that have tried to analyze the value of varicocelectomy in adolescence upon later pregnancy rates in adulthood suggest a benefit from early surgery.11,12 Pajovic and Radojeviv reported at least a 75% pregnancy rate in boys with varicoceles initially operated on between ages 15 and 19 years for abnormal semen parameters, a rate that evidently will become higher once more of this young group of men try to conceive.11 In the earlier study, Salzhauer et al reported a 100% pregnancy rate in 18 Hasidic/ultraorthodox men who were operated on in adolescence and in most cases asymmetry was greater than 10%.12 While Poon et al reported that 67% of those with greater than 15% asymmetry will have persistent or worse asymmetry after a median followup of 21 months,13 Kolon et al instead found that 74% will have catch-up growth to less than 15% asymmetry after a median followup of 39 months.14 As a result, they recommend waiting 3 years to determine if catch-up growth will occur spontaneously. More recently, they take a watch and wait approach toward adolescents, focusing more on TTV than asymmetry, and waiting until these boys reach age 18 years to offer semen analysis. Peak retrograde flow (PRF), asymmetry and TTV measurements obtained on Doppler ultrasound
OPPOSING VIEWS
can all be used to help identify those who need surgery, particularly in boys with earlier Tanner stage disease and in older boys for whom a semen analysis cannot be obtained. Paduch and Niedzielski reported on 17 to 19-year-old boys with grade II and III varicoceles, and noted poorer semen quality in those with greater backflow velocity and greater asymmetry.15 We now have reported in 3 series that the combination of a PRF 38 cm per second or greater and asymmetry 20% or greater, ie “the 20/38 harbinger,” almost uniformly portends persistent or worsening asymmetry. Van Batavia et al found that the “20/38 harbinger” can be extended to those with 15% asymmetry as well.16 While all ultrasonographers have experience measuring PRF in vessels elsewhere in the body, when studying veins of the spermatic cord, it is important that the PRF be obtained with the
647
patient supine and that a satisfactory Valsalva maneuver has been performed. In summary, we have been focused on the prevention of future infertility and prefer to operate with appropriate indications to prevent abnormal semen parameters from developing as opposed to operating in an attempt to reverse established abnormal parameters. We take into account PRF, asymmetry, TTV and testicular consistency when making our decisions. We support the use of semen analysis at ages 17 or 18 years in males who have not been operated on but in whom we still have a concern as to whether surgery should be performed. Kenneth I. Glassberg and Jason P. Van Batavia Department of Urology Columbia University Medical Center New York, New York
REFERENCES 1. Christman MS, Zderic SA, Canning DA et al: Active surveillance of the adolescent with varicocele: predicting semen outcomes from ultrasound. J Urol 2014; 191: 1401. 2. Kozakowski KA, Gjertson CK, Decastro GJ et al: Peak retrograde flow: a novel predictor of persistent, progressive and new onset asymmetry in adolescent varicocele. J Urol 2009; 181: 2717. 3. Moursy EE, ElDahshoury MZ, Hussein MM et al: Dilemma of adolescent varicocele: long-term outcome in patients managed surgically and in patients managed expectantly. J Ped Urol 2013; 9: 1018. 4. Bogaert G, Orye C and De Win G: Pubertal screening and treatment of varicocele do not improve future adult chance of paternity. J Urol 2013; 189: 2298. 5. Li F, Yue H, Yamaguchi K, Okada K et al: Effect of surgical repair on testosterone production in infertile men with varicocele: a meta-analysis. Int J Urol 2012; 19: 149.
6. Kass EJ and Belman AB: Reversal of testicular growth failure by varicocele ligation. J Urol 1987; 137: 475. 7. Haans LCF, Laven JSE, Mali WPTM et al: Testes volumes, semen quality, and hormonal patterns in adolescents with and without a varicocele. Fertil Steril 1991; 56: 731. 8. Cayan S, Akbay E, Bozlu M et al: The effect of varicocele repair on testicular volume in children and adolescents with varicocele. J Urol 2002; 168: 731. 9. Diamond DA, Zurakowski D, Bauer SB et al: Relationship of varicocele grade and testicular hypotrophy to semen parameters in adolescents. J Urol 2007; 178: 1584. 10. Kurtz MP, Rosoklija I, Johnson KL et al: Combined correlation of total testis volume and volume differential with total motile sperm counts in adolescent varicocele. Presented at the annual meeting of the Society for Pediatric Urology/ American Urological Association, Orlando, Florida, May 16-17, 2014.
11. Pajovic B and Radojeviv N: Prospective follow up of fertility after adolescent laparoscopic varicocelectomy. Eur Rev Med Pharmacol Sci 2013; 17: 1060. 12. Salzhauer EW, Sokol A and Glassberg KI: Paternity after adolescent varicocele repair. Pediatrics 2004; 114: 1631. 13. Poon SA, Cjertsen CK, Mercado MA et al: Testicular asymmetry in adolescent varicoceles managed expectantly. J Urol 2010; 183: 731. 14. Kolon TF, Clement MR, Cartwright L et al: Transient asynchronous testicular growth in adolescent males with a varicocele. J Urol 2008; 180: 111. 15. Paduch DA and Niedzielski J: Semen analysis in young men with varicocele: preliminary study. J Urol 1996; 156: 786. 16. Van Batavia JP, Badalato G, Fast A et al: Adolescent varicoceledis the 20/38 harbinger a durable predictor of testicular asymmetry? J Urol 2013; 189: 1897.