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Testicular Catch up Growth: The Impact of Orchiopexy Age
Pediatric Urology Testicular Catch up Growth: The Impact of Orchiopexy Age Sun-Ouck Kim, Eu Chang Hwang, In Sang Hwang, Kyung Jin Oh, Seung Il Jung, Taek Won Kang, Dongdeuk Kwon, Kwangsung Park, and Soo Bang-Ryu OBJECTIVE
MATERIALS AND METHODS
RESULTS
CONCLUSIONS
To compare the long-term follow-up growth of congenital, unilaterally palpable, undescended testes after orchiopexy according to age at the time of surgery. The optimal age for surgical treatment remains controversial. A total of 86 patients (108 testes) between the ages of 1 and 9 years underwent orchiopexy. Patients were divided according to age at the time of surgery: group I, ⬍2 years (n ⫽ 43); group II, 2 ⱕ age ⬍ 5 years (n ⫽ 35); and group III, ⱖ5 years (n ⫽ 30). The boys were then followed for more than 2 years after surgery. Ultrasonography was used for determination of testicular volume. Testicular volume percentage was compared by the equation of (operated testis volume/ normal testis volume ⫻ 100%). Testicular location was the inguinal canal in 92 (85.2%) and lower to the external inguinal ring in 16 (14.8%). Only group I, which received orchiopexy within two years from birth, showed significant recovery of testicular volume at follow-up (P ⬍.05), compared with groups II and III. Orchiopexy performed at less than 2 years from birth was a significant factor for recovery of delayed cryptorchid testicular growth. This result suggests that early orchiopexy improves subsequent testicular catch-up growth. UROLOGY 78: 886 – 890, 2011. © 2011 Elsevier Inc.
U
ndescended testis is the most common congenital anomaly in boys1 and occurs in 3-5% of all full-term male neonates. Prevalence of this condition decreases by spontaneous descent to 1-2% by 6 months of age.2 Failure of bilateral testicular descent results in severely impaired spermatogenesis. If untreated, this results in infertility in adulthood.3 Orchiopexy for bilateral cryptorchidism leads to a higher normal sperm count if surgery was performed before the age of 3 years, compared with surgery after the age of 4 years.4 The overall relative risk of developing testicular cancer in patients with a history of undescended testis appears to be 4.8.5 Therefore, it is generally accepted that retained testes should be brought into the scrotum at some point during early childhood. The optimal age for surgical treatment remains controversial. Histopathological studies of cryptorchid testicular tissue have shown that degenerative changes are already present by 18 months of age.6,7 On the basis of those reports, it is strongly suggested that surgery should be performed within 2 years of life. Until now, most Funding support: This study was supported by a research grant from the Research Institute of Medical Sciences, Chonnam National University (2010-CURIMSDR009). From the Department of Urology, Chonnam National University Medical School, Gwangju, Korea Reprint requests: Soo Bang-Ryu, M.D., Ph.D. Department of Urology, Chonnam National University, Hospital and Medical School, 8, Hak-dong, Dong-ku, Gwangju 501-757, South Korea. E-mail: [email protected] Submitted: February 8, 2011, accepted (with revisions): April 28, 2011
886
© 2011 Elsevier Inc. All Rights Reserved
reports on the potential fertility of cryptorchidism has been evaluated based on histopathological examination by testicular biopsy at orchiopexy.8 However, there is sparse evidence to prove the superiority of the future testicular growth of early orchiopexy. To the best of our knowledge, there are few published prospective studies that randomized boys with undescended testes to surgery at different ages with postoperative follow-up of testicular growth. Because repeat testicular biopsy would seem to be the optimal way to monitor testicular function, this would not be ethically acceptable. Instead, we measured the testicular volume repeatedly, because there is good correlation between the spermatogenic activity of testis and its volume.9 Therefore, we focused on testicular growth before and after orchiopexy according to the difference in age at the time of surgery. We compared the long-term follow-up growth of congenital, unilaterally palpable, undescended testes after orchiopexy according to the age at the time of surgery.
PATIENTS AND METHODS Study Design From January 2007 to December 2008, 198 patients between the ages of 1 and 9 years (mean age, 34.5 months) underwent orchiopexy for unilaterally undescended testes. Among those patients, 108 returned for a follow-up examination of testicular growth. Patients were divided according to age at the time of surgery: group I, ⬍2 years (n ⫽ 43); group II, 2 ⱕ age ⬍ 5 years (n ⫽ 35); and group III, ⱖ5 years (n ⫽ 30). The boys were then 0090-4295/11/$36.00 doi:10.1016/j.urology.2011.04.057
Table 1. Patient characteristics Variables Operation age (y), n(%) ⬍2 2–5 ⱖ5 Laterality, n(%) Lt Rt Location of cryptorchid testis, n (%) Inguinal canal Lower to external inguinal ring
Value 108 (100) 43 (44.4) 35 (32.4) 30 (27.8) 46 (42.6) 62 (57.4) 92 (85.2) 16 (14.8)
followed for more than 2 years after surgery. Ultrasonography was used for determination of testicular volume difference between preoperative and postoperative testicular volume. One pediatric surgeon performed the clinical examination and surgical procedures. We used standard inguinal orchiopexy or primary scrotal approach in some cases.
Definition of Palpable Undescended Testis Congenital undescended testis was defined as an undescended testis in which a scrotal position had not been documented since birth. All testes that could not be brought down to the scrotum at clinical examination by a urological specialist were included. If a testis in a suprascrotal position could be pulled down to the upper part of the scrotum but did not remain there after about 30 seconds of traction—after exhaustion of cremasteric activity—it was also defined as an undescended testis. If it remained in the upper part of the scrotum for approximately 10 seconds or longer after traction was released or if it could be pulled down to the lower part of the scrotal position, it was defined as a retractile testis and was not included.
Testicular Volume Measurement Ultrasound was performed with high-resolution scanners. Testicular volume was calculated using the approximation for a prolapsed ellipsoid, testicular volume ⫽ /6x length ⫻ width ⫻ height. Testicular ultrasonography was followed in each patient for more than 2 years after surgery to measure testicular growth. One special radiologist examined the testicular volume and examiners were blinded to previous results and preliminary data; however, the scars of orchiopexy were clearly visible. Testicular volume percentage was compared by the equation of (operated testis volume/normal testis volume ⫻ 100%).
Statistics SPSS statistical software, version 13.0 (SPSS, Inc., Chicago, IL) was used for statistical analysis. Analysis of variance was used for comparison of the volumes of the operated testes with those of the contralateral testes.
RESULTS Patient characteristics are listed in Table 1. Of the patients participating in the study, 46 (42.6%) had been treated for left-sided and 62 (57.4%) for right-sided undescended testis. On preoperative physical examination, testicular locations were the inguinal canal in 92 (85.2%) and the lower to external inguinal ring in 16 (14.8%). UROLOGY 78 (4), 2011
The contralateral nonoperated testes were located in the scrotal lesion. Testis Volume The age of patients at the time of treatment and the mean testicular volume measured by ultrasonography of the undescended testis in various age groups is shown in Table 2. On preoperative examination, testicular volume for each group was 0.45 ⫾ 0.09 in group I, 0.50 ⫾ 0.11 in group II, and 0.54 ⫾ 0.10 in group III, respectively. On follow-up examination, testicular volume percentage of operated testis compared by the equation of operated testis volume/normal testis volume in each group showed an increase in all groups: group I, from 46.6 to 90; group II, from 68.1 to 78.2; and group III, from 65.7 to 77.6 (P ⬍.05). A significant difference was observed between group I vs group II, and group I vs group III in terms of the testicular volume change after surgery. However, no significant differences were observed between groups II and III (P ⬍.05) (Fig. 1). Only group I, which received orchiopexy within two years from birth, showed a significant recovery of testicular volume at follow-up (P ⬍.05) compared with groups II and III.
COMMENT In the current study, we performed orchiopexy between the ages of 6 months to 11 years in congenital, unilateral cryptorchidism and evaluated subsequent testicular catch-up growth of the operated testis according to age at the time of surgery. We observed a significant increase of testis volume in all groups at the follow-up examination 2 years after surgery. Among the 3 groups, only group I, which received orchiopexy within two years from birth, showed significant recovery of testicular volume at follow-up examination compared with groups II and III. However, no significant differences in recovery of testicular volume were observed between groups II and III, which received orchiopexy at the age of 2 years or older. These findings suggest that testicular growth after orchiopexy for unilateral congenital cryptorchidism shows the best result when the operation is performed within 2 years of age. The current study provides evidence in support of performance of orchiopexy as early possible. Male infertility is one of the serious complications of cryptorchidism, and the average fertility rate is 46% in untreated unilateral cryptorchidism.10 After prepubertal orchiopexy, this rate increases to 59% and in bilateral cryptorchidism it is only 23%.11 There is a common consensus that cryptorchid testis should be corrected as early as possible during childhood to achieve normal spermatogenesis and normal fertility. To date, the most recommendable period for surgery has changed with time and it is still a controversial issue. Because it is not easy to assess the results of early surgery in humans, there has been little evidence to prove the superiority of the future fertility of early orchiopexy before the age of 1 year. However, using histopathological studies of cryptorchid 887
Table 2. Patient age at treatment and mean testicular volume measured by ultrasonography of the testis in various age groups
Preop vol (mL) Postop vol (mL)
⬍2
UDT 2 ⱕ age ⬍ 5
ⱖ5
⬍2
DT 2 ⱕ age ⬍ 5
ⱖ5
0.37 0.78
0.57 0.75
0.61 0.77
0.8 0.87
0.85 0.96
0.93 0.99
UDT ⫽ undescended testis; DT ⫽ descended testis.
Figure 1. Comparison of the percentage of the operated testicular to normal testis.
testicular tissue, Huff et al reported that degenerative changes are already present by 18 months.6 Mizuno et al also attempted to determine the most appropriate period for orchiopexy.12 They performed histologic analyses of undescended testes to evaluate the influence of orchiopexy timing in an experimental cryptorchid rat model. The study results revealed that nonoperated undescended testes showed atrophic and hypospermatogenesis with germ cell apoptosis, whereas operated undescended testes showed development of early elongated spermatids. Early surgical repositioning of the testis into the scrotum before onset of histopathological change seems to decrease the risk of fertility change. There have been few prospective studies that randomized boys with undescended testes to surgery at different ages in view of postoperative follow-up of testicular growth and function.13,14 The ultimate goal of testis repositioning to the scrotum is to attain normal spermatogenesis. To monitor testicular function, performance of invasive testicular biopsy would be required. However, such an invasive practice on young boys would not be ethically acceptable. However, it has been considered that repeat measurement of testicular volume would be a surrogate for testicular function. Lenz et al reported good correlation between spermatogenic activity of the testis and volume of testis.15 To assess the effect of surgery on undescended testes during childhood, they followed testicular growth by physical examination and ultrasonography.15 Ultrasonography is known to be a reliable tool for measurement of testicular volume with high reproducibility during the first year of age16 and is used to determine the 888
volume of the cryptorchid testis before and after testis repositioning as an early marker of the success of the operation. Kollin et al14 conducted a randomized, controlled study to evaluate the question of whether early surgical treatment at 9 months in boys with congenital unilaterally palpable undescended testes is followed by improved growth of the previous cryptorchid testes compared with nontreatment measured by ultrasonography. They conclusively showed that the mean volume of the retained testes was marginally smaller than that of the contralateral scrotal testes from birth. Furthermore, the difference was augmented during the first 6 months of life, even in boys in whom the retained and scrotal testes were of close to equal size at birth. Compared with the nontreated group, surgical treatment at 9 months resulted in partial catch-up growth until 2 years of age. They clearly advocated that early surgery has a beneficial effect on testicular growth. They further reported follow-up of the above-mentioned study in succession and compared the growth of unilateral undescended testes after orchiopexy in their study groups with a longer follow-up of up to 4 years.13 They also confirmed the effectiveness of early surgical treatment on testicular growth in a longer follow-up study. Early surgical treatment at 9 months resulted in partial catch-up of testicular growth until at least the age of 4 years compared with surgery at 3 years. They clearly indicated that early surgery has a positive effect on testicular growth. They also noted the complete absence of growth of testes that are still undescended until the age of 3 years. They suggested that the growth of these testes could not be salvaged by surgery at 3 years because no resumed growth was noted until the end of the follow-up at the age of 4 years. In addition, the ratio between the previously retained testis and its scrotal counterpart showed a significant increase after early surgery, whereas in the late-treated group, this ratio showed a significant decrease even after surgery. These results strongly suggest that surgery at the age of 9 months, rather than 3 years, is beneficial for testicular growth. Our results are consistent with those of the aforementioned randomized study, showing that the testes of the group of subjects who underwent early surgery within 2 years of age showed rapid catch-up growth compared with testes operated on at the age of 2 years or older. Prenatal factors are considered to have a role in impaired testicular growth in cryptorchid testes. The finding that growth of a retained testis is already impaired during the first 6 months of life suggests that surgery during the neonatal period might be required to avoid further damUROLOGY 78 (4), 2011
age to undescended testes. However, it is reported that the cryptorchid testes at birth, which are similar in volume with the contralateral normal positioning testis, showed a significant difference in volume at 6 months.14 This suggests that impaired growth of the cryptorchid testes was caused not only by prenatal factors—increased temperature was also suggested as another probable causative factor.17 Also, in a biopsy study of iatrogenic cryptorchidism after hernia repair, Fening et al revealed that the cryptorchid testes have a decreased number of germ cells per tubule as time duration in a suprascrotal position increases.18 This result indicates that cryptorchid testes, which may undergo secondary adverse changes and accumulated time duration in the suprascrotal environment, have an important role in testicular function.18 In addition, it was reported that surgical treatment at a greater age increases the risk of finding no germ cells in a testicular biopsy compared with whether surgery was performed at a younger age.19 However, this study could prove that neither treatment at the age of 2 years would save normal spermatogenesis nor that treatment at a later age would lead to a worse result in adulthood. Randomized, controlled studies of surgery performed at a later age with a large number of patients and long-term follow-up of testicular growth after surgery at different ages are also needed.
11. Kogan S. Cryptorchidism: Clinical Pediatric Urology, vol 2, 3rd ed. In: Kelalis PP, King LR, Belman AB, eds. Philadelphia: W.B. Saunders; 1992:1050-1083. 12. Mizuno K, Hayashi Y, Kojima Y, et al. Early orchiopexy improves subsequent testicular development and spermatogenesis in the experimental cryptorchid rat model. J Urol. 2008;179:1195-1199. 13. Kollin C, Karpe B, Hesser U, Granholm T, Ritzén EM. Surgical treatment of unilaterally undescended testes: testicular growth after randomization to orchiopexy at age 9 months or 3 years. J Urol. 2007;178:1589-1593. 14. Kollin C, Hesser U, Ritzén EM, Karpe B. Testicular growth from birth to two years of age, and the effect of orchidopexy at age nine months: a randomized, controlled study. Acta Paediatr. 2006;95: 318-324. 15. Lenz S, Giwercman A, Elsborg A, et al. Ultrasonic testicular texture and size in 444 men from the general population: correlation to semen quality. Eur Urol. 1993;24:231-238. 16. Main KM, Toppari J, Suomi AM, et al. Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys. J Clin Endocrinol Metab. 2006;91:2732-2737. 17. Bedford JM. Effects of elevated temperatures on the epididymis and testis: experimental studies. Adv Exp Med Biol. 1991;286:19-32. 18. Fenig DM, Snyder HM, Wu HY, Canning DA, Huff DS. The histopathology of iatrogenic cryptorchid testis: an insight into etiology. J Urol. 2001;165:1258-1261. 19. Cortes D, Thorup JM, 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;55:21-27.
EDITORIAL COMMENT CONCLUSIONS Orchiopexy performed at less than 2 years from birth was a significant factor for recovery of delayed cryptorchid testicular growth. This result suggests that early orchiopexy improves subsequent testicular catchup growth. References 1. Berkowitz GS, Lapinski RH, Dolgin SE, et al. Prevalence and natural history of cryptorchidism. Pediatrics. 1993;92:44-49. 2. Boisen KA, Kaleva M, Main KM, et al. High and increasing prevalence of cryptorchidism in Denmark. Ugeskr Laeger. 2004;22: 4372-4375. 3. Lee PA, Coughlin MT. Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data. Horm Res. 2001;55:28-32. 4. Engeler DS, Hösli PO, John H, et al. Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome. Urology. 2000;56:144-148. 5. Dieckmann KP, Pichlmeier U. Clinical epidemiology of testicular germ cell tumors. World J Urol. 2004;22:2-14. 6. Huff DS, Hadziselimovic F, Snyder HM 3rd, Duckett JW, Keating MA. Postnatal testicular maldevelopment in unilateral cryptorchidism. J Urol. 1989;142:546-548. 7. Hadziselimovic F, Herzog B. The importance of both an early orchidopexy and germ cell maturation for fertility. Lancet. 2001; 358:1156-1157. 8. McAleer IM, Packer MG, Kaplan GW, et al. Fertility index analysis in cryptorchidism. J Urol. 1995;153:1255-1258. 9. Noh PH, Cooper CS, Snyder HM 3rd, et al. Testicular volume does not predict germ cell count in patients with cryptorchidism. J Urol. 2000;163:593-596. 10. Lipshultz LI. Cryptorchidism in the subfertile male. Fertil Steril. 1976;27:609-620.
UROLOGY 78 (4), 2011
The authors have concluded that if orchidopexy is performed earlier than 2 years of age, it improves subsequent testicular catch-up growth. To support this conclusion, the data must be, at a minimum, adjusted for age and standard deviation, eg, by using the testicular volume chart.1 In addition, the authors should provide the original data of testicular volumes, which may provide adequate statistical support for the author’s hypothesis. However, even with the above considerations, it is known that 10% of unilateral cryptorchid boys, independent of successful outcome and timely performance of surgery, will develop azoospermia.2 This strongly indicates that, even if descended, the contralateral testis at the time of surgery is already abnormal. As many as 70% of contralateral descended testes were reported to show impaired development of Ad spermatogonia, indicating additionally that unilateral cryptorchidism is a bilateral disease.3 Currently, the single most reliable test for fertility outcome is a testicular biopsy. Therefore, performing a testicular biopsy in cryptorchid boys who have endocrine andrological problems leading to infertility is highly recommended. In addition, because testicular volume does not accurately predict the germ cell count in patients with undescended testes, this parameter cannot be used to select patients for postorchiopexy hormonal therapy. Testicular volume cannot replace the predictive value of testicular biopsy in the modern management of cryptorchidism, as improperly quoted (see Introduction) by the authors. The authors correctly stated that the ultimate goal for testes relocation into the scrotum is to obtain normal spermatogenesis. This reviewer agrees with the author’s statement that their study neither proves that treatment at the age of two years would promote normal spermatogenesis nor that the treatment at the later age would lead to a worse result in adulthood. 889
MATERIALS AND METHODS
RESULTS
CONCLUSIONS
To compare the long-term follow-up growth of congenital, unilaterally palpable, undescended testes after orchiopexy according to age at the time of surgery. The optimal age for surgical treatment remains controversial. A total of 86 patients (108 testes) between the ages of 1 and 9 years underwent orchiopexy. Patients were divided according to age at the time of surgery: group I, ⬍2 years (n ⫽ 43); group II, 2 ⱕ age ⬍ 5 years (n ⫽ 35); and group III, ⱖ5 years (n ⫽ 30). The boys were then followed for more than 2 years after surgery. Ultrasonography was used for determination of testicular volume. Testicular volume percentage was compared by the equation of (operated testis volume/ normal testis volume ⫻ 100%). Testicular location was the inguinal canal in 92 (85.2%) and lower to the external inguinal ring in 16 (14.8%). Only group I, which received orchiopexy within two years from birth, showed significant recovery of testicular volume at follow-up (P ⬍.05), compared with groups II and III. Orchiopexy performed at less than 2 years from birth was a significant factor for recovery of delayed cryptorchid testicular growth. This result suggests that early orchiopexy improves subsequent testicular catch-up growth. UROLOGY 78: 886 – 890, 2011. © 2011 Elsevier Inc.
U
ndescended testis is the most common congenital anomaly in boys1 and occurs in 3-5% of all full-term male neonates. Prevalence of this condition decreases by spontaneous descent to 1-2% by 6 months of age.2 Failure of bilateral testicular descent results in severely impaired spermatogenesis. If untreated, this results in infertility in adulthood.3 Orchiopexy for bilateral cryptorchidism leads to a higher normal sperm count if surgery was performed before the age of 3 years, compared with surgery after the age of 4 years.4 The overall relative risk of developing testicular cancer in patients with a history of undescended testis appears to be 4.8.5 Therefore, it is generally accepted that retained testes should be brought into the scrotum at some point during early childhood. The optimal age for surgical treatment remains controversial. Histopathological studies of cryptorchid testicular tissue have shown that degenerative changes are already present by 18 months of age.6,7 On the basis of those reports, it is strongly suggested that surgery should be performed within 2 years of life. Until now, most Funding support: This study was supported by a research grant from the Research Institute of Medical Sciences, Chonnam National University (2010-CURIMSDR009). From the Department of Urology, Chonnam National University Medical School, Gwangju, Korea Reprint requests: Soo Bang-Ryu, M.D., Ph.D. Department of Urology, Chonnam National University, Hospital and Medical School, 8, Hak-dong, Dong-ku, Gwangju 501-757, South Korea. E-mail: [email protected] Submitted: February 8, 2011, accepted (with revisions): April 28, 2011
886
© 2011 Elsevier Inc. All Rights Reserved
reports on the potential fertility of cryptorchidism has been evaluated based on histopathological examination by testicular biopsy at orchiopexy.8 However, there is sparse evidence to prove the superiority of the future testicular growth of early orchiopexy. To the best of our knowledge, there are few published prospective studies that randomized boys with undescended testes to surgery at different ages with postoperative follow-up of testicular growth. Because repeat testicular biopsy would seem to be the optimal way to monitor testicular function, this would not be ethically acceptable. Instead, we measured the testicular volume repeatedly, because there is good correlation between the spermatogenic activity of testis and its volume.9 Therefore, we focused on testicular growth before and after orchiopexy according to the difference in age at the time of surgery. We compared the long-term follow-up growth of congenital, unilaterally palpable, undescended testes after orchiopexy according to the age at the time of surgery.
PATIENTS AND METHODS Study Design From January 2007 to December 2008, 198 patients between the ages of 1 and 9 years (mean age, 34.5 months) underwent orchiopexy for unilaterally undescended testes. Among those patients, 108 returned for a follow-up examination of testicular growth. Patients were divided according to age at the time of surgery: group I, ⬍2 years (n ⫽ 43); group II, 2 ⱕ age ⬍ 5 years (n ⫽ 35); and group III, ⱖ5 years (n ⫽ 30). The boys were then 0090-4295/11/$36.00 doi:10.1016/j.urology.2011.04.057
Table 1. Patient characteristics Variables Operation age (y), n(%) ⬍2 2–5 ⱖ5 Laterality, n(%) Lt Rt Location of cryptorchid testis, n (%) Inguinal canal Lower to external inguinal ring
Value 108 (100) 43 (44.4) 35 (32.4) 30 (27.8) 46 (42.6) 62 (57.4) 92 (85.2) 16 (14.8)
followed for more than 2 years after surgery. Ultrasonography was used for determination of testicular volume difference between preoperative and postoperative testicular volume. One pediatric surgeon performed the clinical examination and surgical procedures. We used standard inguinal orchiopexy or primary scrotal approach in some cases.
Definition of Palpable Undescended Testis Congenital undescended testis was defined as an undescended testis in which a scrotal position had not been documented since birth. All testes that could not be brought down to the scrotum at clinical examination by a urological specialist were included. If a testis in a suprascrotal position could be pulled down to the upper part of the scrotum but did not remain there after about 30 seconds of traction—after exhaustion of cremasteric activity—it was also defined as an undescended testis. If it remained in the upper part of the scrotum for approximately 10 seconds or longer after traction was released or if it could be pulled down to the lower part of the scrotal position, it was defined as a retractile testis and was not included.
Testicular Volume Measurement Ultrasound was performed with high-resolution scanners. Testicular volume was calculated using the approximation for a prolapsed ellipsoid, testicular volume ⫽ /6x length ⫻ width ⫻ height. Testicular ultrasonography was followed in each patient for more than 2 years after surgery to measure testicular growth. One special radiologist examined the testicular volume and examiners were blinded to previous results and preliminary data; however, the scars of orchiopexy were clearly visible. Testicular volume percentage was compared by the equation of (operated testis volume/normal testis volume ⫻ 100%).
Statistics SPSS statistical software, version 13.0 (SPSS, Inc., Chicago, IL) was used for statistical analysis. Analysis of variance was used for comparison of the volumes of the operated testes with those of the contralateral testes.
RESULTS Patient characteristics are listed in Table 1. Of the patients participating in the study, 46 (42.6%) had been treated for left-sided and 62 (57.4%) for right-sided undescended testis. On preoperative physical examination, testicular locations were the inguinal canal in 92 (85.2%) and the lower to external inguinal ring in 16 (14.8%). UROLOGY 78 (4), 2011
The contralateral nonoperated testes were located in the scrotal lesion. Testis Volume The age of patients at the time of treatment and the mean testicular volume measured by ultrasonography of the undescended testis in various age groups is shown in Table 2. On preoperative examination, testicular volume for each group was 0.45 ⫾ 0.09 in group I, 0.50 ⫾ 0.11 in group II, and 0.54 ⫾ 0.10 in group III, respectively. On follow-up examination, testicular volume percentage of operated testis compared by the equation of operated testis volume/normal testis volume in each group showed an increase in all groups: group I, from 46.6 to 90; group II, from 68.1 to 78.2; and group III, from 65.7 to 77.6 (P ⬍.05). A significant difference was observed between group I vs group II, and group I vs group III in terms of the testicular volume change after surgery. However, no significant differences were observed between groups II and III (P ⬍.05) (Fig. 1). Only group I, which received orchiopexy within two years from birth, showed a significant recovery of testicular volume at follow-up (P ⬍.05) compared with groups II and III.
COMMENT In the current study, we performed orchiopexy between the ages of 6 months to 11 years in congenital, unilateral cryptorchidism and evaluated subsequent testicular catch-up growth of the operated testis according to age at the time of surgery. We observed a significant increase of testis volume in all groups at the follow-up examination 2 years after surgery. Among the 3 groups, only group I, which received orchiopexy within two years from birth, showed significant recovery of testicular volume at follow-up examination compared with groups II and III. However, no significant differences in recovery of testicular volume were observed between groups II and III, which received orchiopexy at the age of 2 years or older. These findings suggest that testicular growth after orchiopexy for unilateral congenital cryptorchidism shows the best result when the operation is performed within 2 years of age. The current study provides evidence in support of performance of orchiopexy as early possible. Male infertility is one of the serious complications of cryptorchidism, and the average fertility rate is 46% in untreated unilateral cryptorchidism.10 After prepubertal orchiopexy, this rate increases to 59% and in bilateral cryptorchidism it is only 23%.11 There is a common consensus that cryptorchid testis should be corrected as early as possible during childhood to achieve normal spermatogenesis and normal fertility. To date, the most recommendable period for surgery has changed with time and it is still a controversial issue. Because it is not easy to assess the results of early surgery in humans, there has been little evidence to prove the superiority of the future fertility of early orchiopexy before the age of 1 year. However, using histopathological studies of cryptorchid 887
Table 2. Patient age at treatment and mean testicular volume measured by ultrasonography of the testis in various age groups
Preop vol (mL) Postop vol (mL)
⬍2
UDT 2 ⱕ age ⬍ 5
ⱖ5
⬍2
DT 2 ⱕ age ⬍ 5
ⱖ5
0.37 0.78
0.57 0.75
0.61 0.77
0.8 0.87
0.85 0.96
0.93 0.99
UDT ⫽ undescended testis; DT ⫽ descended testis.
Figure 1. Comparison of the percentage of the operated testicular to normal testis.
testicular tissue, Huff et al reported that degenerative changes are already present by 18 months.6 Mizuno et al also attempted to determine the most appropriate period for orchiopexy.12 They performed histologic analyses of undescended testes to evaluate the influence of orchiopexy timing in an experimental cryptorchid rat model. The study results revealed that nonoperated undescended testes showed atrophic and hypospermatogenesis with germ cell apoptosis, whereas operated undescended testes showed development of early elongated spermatids. Early surgical repositioning of the testis into the scrotum before onset of histopathological change seems to decrease the risk of fertility change. There have been few prospective studies that randomized boys with undescended testes to surgery at different ages in view of postoperative follow-up of testicular growth and function.13,14 The ultimate goal of testis repositioning to the scrotum is to attain normal spermatogenesis. To monitor testicular function, performance of invasive testicular biopsy would be required. However, such an invasive practice on young boys would not be ethically acceptable. However, it has been considered that repeat measurement of testicular volume would be a surrogate for testicular function. Lenz et al reported good correlation between spermatogenic activity of the testis and volume of testis.15 To assess the effect of surgery on undescended testes during childhood, they followed testicular growth by physical examination and ultrasonography.15 Ultrasonography is known to be a reliable tool for measurement of testicular volume with high reproducibility during the first year of age16 and is used to determine the 888
volume of the cryptorchid testis before and after testis repositioning as an early marker of the success of the operation. Kollin et al14 conducted a randomized, controlled study to evaluate the question of whether early surgical treatment at 9 months in boys with congenital unilaterally palpable undescended testes is followed by improved growth of the previous cryptorchid testes compared with nontreatment measured by ultrasonography. They conclusively showed that the mean volume of the retained testes was marginally smaller than that of the contralateral scrotal testes from birth. Furthermore, the difference was augmented during the first 6 months of life, even in boys in whom the retained and scrotal testes were of close to equal size at birth. Compared with the nontreated group, surgical treatment at 9 months resulted in partial catch-up growth until 2 years of age. They clearly advocated that early surgery has a beneficial effect on testicular growth. They further reported follow-up of the above-mentioned study in succession and compared the growth of unilateral undescended testes after orchiopexy in their study groups with a longer follow-up of up to 4 years.13 They also confirmed the effectiveness of early surgical treatment on testicular growth in a longer follow-up study. Early surgical treatment at 9 months resulted in partial catch-up of testicular growth until at least the age of 4 years compared with surgery at 3 years. They clearly indicated that early surgery has a positive effect on testicular growth. They also noted the complete absence of growth of testes that are still undescended until the age of 3 years. They suggested that the growth of these testes could not be salvaged by surgery at 3 years because no resumed growth was noted until the end of the follow-up at the age of 4 years. In addition, the ratio between the previously retained testis and its scrotal counterpart showed a significant increase after early surgery, whereas in the late-treated group, this ratio showed a significant decrease even after surgery. These results strongly suggest that surgery at the age of 9 months, rather than 3 years, is beneficial for testicular growth. Our results are consistent with those of the aforementioned randomized study, showing that the testes of the group of subjects who underwent early surgery within 2 years of age showed rapid catch-up growth compared with testes operated on at the age of 2 years or older. Prenatal factors are considered to have a role in impaired testicular growth in cryptorchid testes. The finding that growth of a retained testis is already impaired during the first 6 months of life suggests that surgery during the neonatal period might be required to avoid further damUROLOGY 78 (4), 2011
age to undescended testes. However, it is reported that the cryptorchid testes at birth, which are similar in volume with the contralateral normal positioning testis, showed a significant difference in volume at 6 months.14 This suggests that impaired growth of the cryptorchid testes was caused not only by prenatal factors—increased temperature was also suggested as another probable causative factor.17 Also, in a biopsy study of iatrogenic cryptorchidism after hernia repair, Fening et al revealed that the cryptorchid testes have a decreased number of germ cells per tubule as time duration in a suprascrotal position increases.18 This result indicates that cryptorchid testes, which may undergo secondary adverse changes and accumulated time duration in the suprascrotal environment, have an important role in testicular function.18 In addition, it was reported that surgical treatment at a greater age increases the risk of finding no germ cells in a testicular biopsy compared with whether surgery was performed at a younger age.19 However, this study could prove that neither treatment at the age of 2 years would save normal spermatogenesis nor that treatment at a later age would lead to a worse result in adulthood. Randomized, controlled studies of surgery performed at a later age with a large number of patients and long-term follow-up of testicular growth after surgery at different ages are also needed.
11. Kogan S. Cryptorchidism: Clinical Pediatric Urology, vol 2, 3rd ed. In: Kelalis PP, King LR, Belman AB, eds. Philadelphia: W.B. Saunders; 1992:1050-1083. 12. Mizuno K, Hayashi Y, Kojima Y, et al. Early orchiopexy improves subsequent testicular development and spermatogenesis in the experimental cryptorchid rat model. J Urol. 2008;179:1195-1199. 13. Kollin C, Karpe B, Hesser U, Granholm T, Ritzén EM. Surgical treatment of unilaterally undescended testes: testicular growth after randomization to orchiopexy at age 9 months or 3 years. J Urol. 2007;178:1589-1593. 14. Kollin C, Hesser U, Ritzén EM, Karpe B. Testicular growth from birth to two years of age, and the effect of orchidopexy at age nine months: a randomized, controlled study. Acta Paediatr. 2006;95: 318-324. 15. Lenz S, Giwercman A, Elsborg A, et al. Ultrasonic testicular texture and size in 444 men from the general population: correlation to semen quality. Eur Urol. 1993;24:231-238. 16. Main KM, Toppari J, Suomi AM, et al. Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys. J Clin Endocrinol Metab. 2006;91:2732-2737. 17. Bedford JM. Effects of elevated temperatures on the epididymis and testis: experimental studies. Adv Exp Med Biol. 1991;286:19-32. 18. Fenig DM, Snyder HM, Wu HY, Canning DA, Huff DS. The histopathology of iatrogenic cryptorchid testis: an insight into etiology. J Urol. 2001;165:1258-1261. 19. Cortes D, Thorup JM, 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;55:21-27.
EDITORIAL COMMENT CONCLUSIONS Orchiopexy performed at less than 2 years from birth was a significant factor for recovery of delayed cryptorchid testicular growth. This result suggests that early orchiopexy improves subsequent testicular catchup growth. References 1. Berkowitz GS, Lapinski RH, Dolgin SE, et al. Prevalence and natural history of cryptorchidism. Pediatrics. 1993;92:44-49. 2. Boisen KA, Kaleva M, Main KM, et al. High and increasing prevalence of cryptorchidism in Denmark. Ugeskr Laeger. 2004;22: 4372-4375. 3. Lee PA, Coughlin MT. Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data. Horm Res. 2001;55:28-32. 4. Engeler DS, Hösli PO, John H, et al. Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome. Urology. 2000;56:144-148. 5. Dieckmann KP, Pichlmeier U. Clinical epidemiology of testicular germ cell tumors. World J Urol. 2004;22:2-14. 6. Huff DS, Hadziselimovic F, Snyder HM 3rd, Duckett JW, Keating MA. Postnatal testicular maldevelopment in unilateral cryptorchidism. J Urol. 1989;142:546-548. 7. Hadziselimovic F, Herzog B. The importance of both an early orchidopexy and germ cell maturation for fertility. Lancet. 2001; 358:1156-1157. 8. McAleer IM, Packer MG, Kaplan GW, et al. Fertility index analysis in cryptorchidism. J Urol. 1995;153:1255-1258. 9. Noh PH, Cooper CS, Snyder HM 3rd, et al. Testicular volume does not predict germ cell count in patients with cryptorchidism. J Urol. 2000;163:593-596. 10. Lipshultz LI. Cryptorchidism in the subfertile male. Fertil Steril. 1976;27:609-620.
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The authors have concluded that if orchidopexy is performed earlier than 2 years of age, it improves subsequent testicular catch-up growth. To support this conclusion, the data must be, at a minimum, adjusted for age and standard deviation, eg, by using the testicular volume chart.1 In addition, the authors should provide the original data of testicular volumes, which may provide adequate statistical support for the author’s hypothesis. However, even with the above considerations, it is known that 10% of unilateral cryptorchid boys, independent of successful outcome and timely performance of surgery, will develop azoospermia.2 This strongly indicates that, even if descended, the contralateral testis at the time of surgery is already abnormal. As many as 70% of contralateral descended testes were reported to show impaired development of Ad spermatogonia, indicating additionally that unilateral cryptorchidism is a bilateral disease.3 Currently, the single most reliable test for fertility outcome is a testicular biopsy. Therefore, performing a testicular biopsy in cryptorchid boys who have endocrine andrological problems leading to infertility is highly recommended. In addition, because testicular volume does not accurately predict the germ cell count in patients with undescended testes, this parameter cannot be used to select patients for postorchiopexy hormonal therapy. Testicular volume cannot replace the predictive value of testicular biopsy in the modern management of cryptorchidism, as improperly quoted (see Introduction) by the authors. The authors correctly stated that the ultimate goal for testes relocation into the scrotum is to obtain normal spermatogenesis. This reviewer agrees with the author’s statement that their study neither proves that treatment at the age of two years would promote normal spermatogenesis nor that the treatment at the later age would lead to a worse result in adulthood. 889