- Email: [email protected]
Surgical Treatment of Unilaterally Undescended Testes: Testicular Growth After Randomization to Orchiopexy at Age 9 Months or 3 Years
Surgical Treatment of Unilaterally Undescended Testes: Testicular Growth After Randomization to Orchiopexy at Age 9 Months or 3 Years Claude Kollin,* Bengt Karpe, Ulf Hesser, Tina Granholm and E. Martin Ritzén From the Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden
Purpose: We compared the growth of congenital, unilaterally undescended testes following orchiopexy at age 9 months or 3 years. Materials and Methods: Patients were randomized to surgery at age 9 months (72) or 3 years (83). Testicular volume was measured by ultrasonography at ages 6, 12, 24, 39 and 48 months. Results: Orchiopexy at age 9 months resulted in an increase in testicular volume at subsequent measurements at ages 2, 3 and 4 years compared to the volume at 6 months (p ⬍0.001). In contrast, no significant growth was noted in the group treated at age 3 years. The improved testicular growth after early orchiopexy was also demonstrated by a gradual increase in the ratio of the previously retained testis and the scrotal testis in individual boys from 6 months to 4 years (0.68 to 0.81, p ⬍0.001). For the late treatment group a significant decrease in this ratio was noted during the same period (0.68 to 0.56, p ⬍0.01). Conclusions: Surgical treatment at 9 months resulted in partial catch-up of testicular growth until at least age 4 years compared to surgery at 3 years, clearly indicating that early surgery has a beneficial effect on testicular growth. Since testicular volume is an approximate indirect measure of spermatogenic activity, this gives hope that orchiopexy at this age may improve future spermatogenesis. Key Words: testis; cryptorchidism; infertility, male; spermatozoa; abnormalities
ndescended testes is the most common congenital anomaly in boys.1 The prevalence in full-term newborns (birth weight 2,500 gm or greater) is approximately 3%, decreasing by spontaneous descent to 1% to 2% by age 6 months. The incidence seems to be increasing in Denmark, suggesting an environmental influences on genital development.2 Unilateral cryptorchidism accounts for about 85% of all cases.1 Failure of bilateral testicular descent results in severely impaired spermatogenesis. If untreated, this results in infertility in adulthood.3 In agreement with these studies a decreased paternity rate has been observed after surgically treated bilateral cryptorchidism but not after unilateral cryptorchidism.4 Orchiopexy for bilateral cryptorchidism leads to a higher normal sperm count if surgery was performed before age 3 years compared to surgery after age 4 years.5 Therefore, it is generally accepted that retained testes should be brought into the scrotum at some time during early childhood. The means of accomplishing this are hormonal or surgical treatment. Two modes of hormone treatment have been suggested but each has been of doubtful efficacy and safety.
U
Study received approval from the Committee for Ethics in Medical Research at Karolinska Institutet. Supported by Stiftelsen Frimurare Barnhuset, Sällskapet Barnavård, Kronprinsessans Lovisas och Axel Tielmans fond för barnsjukvård and Sven Jerrings Fond. * Correspondence: Department of Woman and Child Health, Karolinska Institutet, Pediatric Surgery (Q3:03), Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden (telephone: ⫹46 8 51777714; FAX: ⫹ 46 8 51777715; e-mail: [email protected]).
0022-5347/07/1784-1589/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
Several groups have disputed the effectiveness of gonadotropin releasing hormone or human chorionic gonadotropin treatment.6 Therefore, surgical positioning of the retained testes into the scrotum has gained renewed popularity.7 However, the optimal age for surgical treatment remains controversial. Based on histopathological studies it was suggested that surgery should be performed within the first 2 years of life.8,9 To our knowledge there are no published, prospective studies that randomized boys with undescended testes to surgery at different ages with postoperative followup of testicular growth and function. Since the final goal of treatment is to achieve normal adult spermatogenesis, repeat testicular biopsies would seem to be the optimal way to monitor treatment success. However, this would not be ethically acceptable. Instead, repeat measurements of testicular volume may serve as a surrogate since there is a good correlation between the spermatogenic activity of a testicle, and its volume in adults10,11 and in prepubertal children.12 Therefore, we focused on testicular growth before and after orchiopexy at age 9 months or 3 years a followup to age 4 years. Ultrasonography is a reliable method for determining testicular volume13 with precision and reproducibility also during the first years of life.14 Thus, an accurate determination of the volume of the retained and scrotal testes using ultrasonography before and repeatedly after treatment seems to be acceptable as an early marker of the success of treatment. This report is the followup of a previous study in which patients with and without orchiopexy at age 9 months were followed until age 24 months.15 Further details of study
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Vol. 178, 1589-1593, October 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.03.173
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SURGICAL TREATMENT OF UNILATERALLY UNDESCENDED TESTES
design, surgical procedure, definitions and methods can be found in the previous publication. PATIENTS AND METHODS This study began in 1998 at the Astrid Lindgren Children’s Hospital, Karolinska University Hospital. A total of 164 boys with unilateral palpable undescended testis were included in the study, of whom 117 were recruited at ages 0 to 3 weeks and 47 were referred later and included at age 6 months. According to neonatal records the latter boys had unilaterally palpable undescended testes also at birth. At age 6 months the boys were randomized to surgery at age 9 months (72) or 3 years (83). Nine boys who were included at birth withdrew before age 6 months due to lack of parental compliance and they were consequently not randomized. Some patients did not undergo all ultrasound examinations because they missed appointments, were ill or came too late for ultrasonography. Clinical and ultrasound examinations were used to define the position and volume of the 2 testicles at ages 0 to 3 weeks, 2 months (no ultrasonography), 6 months, and 12, 24, 36 and 39 months in the late treatment group, and 48 and 60 months at all time points ⫾ 2 weeks. The number of ultrasound examinations varied somewhat at different time points, although patients remained in the study. Blood samples for hormone measurements were collected at each visit and at surgery biopsy was done for histological evaluation (data not shown). One pediatric surgeon (CK) performed more than 95% of the clinical examinations and surgical procedures. Inclusion criteria were congenital unilateral palpable undescended testis at ages 0 to 3 weeks or at 6 months. Exclusion criteria were spontaneous descent, recognized syndromes, other birth defects or other pathological conditions afflicting the external genitalia, prematurity (less than 37 weeks of gestation) and prior groin surgery. Definition of Palpable Undescended Testes All testes that could not be brought down into the scrotum at clinical examination were included. If a testis in a suprascrotal position could be pulled down to the upper part of scrotum but did not remain there after about 30 seconds of traction (after the 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 it could be pulled down to the lower part of the scrotal position, it was defined as a retractile testis and not included. Ultrasound was performed with high resolution scanners. Testicular volume was calculated using the approximation for a prolapsed ellipsoid, V ⫽ /6 ⫻ length ⫻ width ⫻ height. The majority of procedures were performed by 1 pediatric radiologist (UH). Examiners were blinded to previous results and preliminary data but obviously the scars of orchiopexy were clearly visible. At the 4-year ultrasound this was not a problem since a 1-year-old scar could not be distinguished from a 3-year-old scar. All parts of this study were approved by the Committee for Ethics in Medical Research at the Karolinska Institutet. Statistical Methods The measured volume of the testicles of 164 boys was analyzed with a generalized linear model for longitudinal data. Due to skewed distribution of residuals the logarithm of testicular volumes was used for calculations. Missing values were assumed to be missing at random. Due to the number of missing values data were analyzed with PROC MIXED in SAS®. RESULTS Testicular volumes previously reported up to age 2 years15 are included in the total numbers to show the full development from ages birth to 4 years. Testicular size was determined in the retained and the scrotal testis in each patient. Development of the Scrotal and Retained Testes From Birth to 6 Months Between ages 0 to 3 weeks and 6 months median volume of the normally descended testis increased from 0.30 to 0.51 ml (p ⬍0.001, see table and fig. 1). The retained testis increased from 0.25 to 0.35 ml (p ⬍0.001, see table and fig. 2). There was a significant difference in median volume between the scrotal and retained testes at ages 0 to 3 weeks and 6 months (each p ⬍0.001). Thus, during the first 6 months postnatally the volume of the descended testis increased by 70%, while the increase in the retained testis was only 40%.
Volume at various ages of retained and scrotal testes, and ratio between them in early and late treated groups Undescended Testis
Descended Testis
Undescended/Descended
Age group
No. Testes
Median Vol (ml)
No. Testes
Median Vol (ml)
No. Testes
Median
0–3 Wks 6 Mos 12 Mos: Early surgery Late surgery 24 Mos: Early surgery Late surgery 36 Mos: Early surgery Late surgery 48 Mos: Early surgery Late surgery
110 139
0.25 0.35
112 144
0.30 0.51
110 139
0.84 0.68
67 72
0.38 0.33
67 72
0.51 0.51
67 72
0.74 0.66
53 63
0.42 0.33
54 66
0.56 0.54
53 63
0.73 0.60
43 44
0.49 0.38
44 45
0.59 0.58
43 44
0.86 0.64
33 44
0.50 0.38
33 44
0.65 0.64
33 44
0.80 0.56
Orchiopexy was performed at ages 9 months and 3 years.
SURGICAL TREATMENT OF UNILATERALLY UNDESCENDED TESTES
FIG. 1. Development of volume of initially retained testes in boys with palpable unilaterally undescended testes from ages 0 to 3 weeks (w) to 4 years (y). At age 6 months (mo) all boys were randomized to orchiopexy at 9 months (72) or 3 years (83). At ages 2, 3 and 4 years there was significant difference in median volume of initially retained testes between early and late treated groups (p ⬍0.001). Curves show median and 95% CI. Values indicate number of testes.
Further Growth of the Scrotal Testes From 6 Months to 4 Years Between 6 months and 4 years an increase in the median volume of the scrotal testes was noted (p ⬍0.001, see table and fig. 1). There were no significant differences in scrotal testis volume between the 2 groups at any age. Further Growth of The Retained Testes From 6 Months to 4 Years and the Influence of Orchiopexy at 9 Months or 3 Years Orchiopexy at age 9 months resulted in an increase in median testicular volume from 0.35 ml at 6 months to 0.42 ml at 2 years, 0.49 at 3 years and 0.50 ml at 4 years (p ⬍0.001, see table and fig. 1). Thus, orchiopexy was followed by significant partial catch-up growth. In contrast, during the
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FIG. 3. Development of volume of initially retained testes in boys with palpable unilaterally undescended testes from ages 0 to 3 weeks (w) to 4 years (y). At age 6 months (mo) all boys were randomized to orchiopexy at 9 months (72) or 3 years (83). In early treated group there was increase in median ratio from ages 6 months to 3 and 4 years (p ⬍0.001). At ages 2, 3 and 4 years there was significant difference in this ratio between early and late treated groups, again showing partial catch-up growth of early treated testis (p ⬍0.001). Curves show median and 95% CI. Values indicate number of ultrasound examinations.
same period there was no significant growth of the retained testes before or after surgery in the group randomized to orchiopexy at 3 years. At ages 2, 3 and 4 years there were significant differences in median volume between testes that were surgically treated at 9 months compared to the group with treatment at age 3 years (p ⬍0.001, see table). The volume of the initially retained testis in each group still had not reached the size of its scrotal counterpart on any measurements at age 2, 3 or 4 years. Retained-to-Scrotal Testis Ratio The ratio of the volume of the undescended testis and its contralateral scrotal counterpart provided a direct comparison of the 2 testes in individual boys. Thus, it is an index of the degree of growth deficit of the retained testis. In the early treatment group operated at 9 months there was an increase in the median ratio from 0.68 at 6 months to 0.81 at 4 years (p ⬍0.001). In contrast, a decrease in the median ratio was noted in the late treatment group (at 3 years) from 0.68 at 6 months to 0.56 at 4 years (p ⬍0.001, see table and fig. 3). At ages 2, 3 and 4 years there were significant differences in this ratio between the early and late treatment groups, again demonstrating the partial catch-up growth of early treated testes (p ⬍0.001). DISCUSSION
FIG. 2. Development of volume of initially retained testes in boys with palpable unilaterally undescended testes from ages 0 to 3 weeks (w) to 4 years (y). At age 6 months (mo) all boys were randomized to orchiopexy at 9 months (72) or 3 years (83). There was no significant difference in scrotal testicular volume between early and late treated groups at any age. Curves show median and 95% CI. Values indicate number of testes.
There is a general consensus that cryptorchidism should be treated in early childhood to achieve normal spermatogenesis and normal fertility. In the search for improvements interest has focused on age at treatment. In the classic histopathological studies of Hedinger the number of spermatogonia per tubular cross-section was decreased in undescended testes from age 2 years and thereafter compared to a normal population.16 This was later confirmed by others. However, this proves neither that treatment at age 1 year
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SURGICAL TREATMENT OF UNILATERALLY UNDESCENDED TESTES
would save normal spermatogenesis nor that treatment at a later age would lead to a worse result in adulthood. Thus, prospective, randomized, controlled studies of the effect of orchiopexy in infancy compared to later surgery are needed. In the current study boys were randomized to surgical treatment at age 9 months or 3 years. A way of assessing the effect of surgery on undescended testes during childhood would be to follow testicular growth. In normal boys testicular volume almost doubles during the first 3 months of life with little or no further increase between ages 3 and 18 months.14 Also, during the following years testicular growth is slow, as demonstrated in the current study by the development of the scrotal testes during the first 4 years of life (see table and fig. 2), showing slow, statistically nonsignificant growth during the second and fourth years of life. Thus, comparing the volume of the previously retained testes during the first year after surgery at age 9 or 36 months should be a way to compare the effectiveness of treatment at these 2 ages. Also, a comparison of the ratio between the retained and the scrotal testis in the 2 groups can be a good measurement of therapeutic success. To our knowledge this prospective, randomized study shows for the first time that early orchiopexy at age 9 months results in significant catch-up growth of the initially retained testes up to age 4 years, which contrasts with the complete absence of growth of testes that are still undescended until age 3 years. The growth of these latter testes could not be salvaged by surgery at 3 years. No resumed growth was noted until the end of the current followup at age 4 years. Also, the ratio between the previously retained testis and its scrotal counterpart showed a significant increase following early surgery, while in the late treated group this ratio showed a significant decrease even after surgery. These results strongly suggest that surgery at age 9 months rather than 3 years is beneficial for testicular growth. Our results are consistent with those in previous studies showing that the volume of the retained testes is usually less than volume of scrotal testes with the difference persisting into adulthood.17,18 However, those studies were not prospective with measurements of testicular size at birth, nor did they assess testicular growth during the first months of life, a period when the testes show more activity than at any other time before puberty. We found a significant difference in volume between scrotal and retained testes at the first measurement at age 0 to 3 weeks. This suggests that prenatal factors have a role in impaired testicular growth. However, in the first report of this study it was shown that retained testes that at birth were close to equal in volume with the contralateral scrotal testis showing a significant difference in volume at 6 months.15 This suggests that impaired growth of the retained testis was not only due to prenatal factors. Increased temperature was suggested to be the most probable causative factor.19 Also, a biopsy study of iatrogenic cryptorchidism after hernia repair showed that these testes have a decreased number of germ cells per tubular cross-section as time in a suprascrotal position increases, indicating that these testes undergo secondary adverse changes and accumulated time in the suprascrotal environment has an important role.20 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 to whether surgery was performed at a younger age.9
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 damage to undescended testes. However, before beginning such a study methods must be developed to distinguish testes that will descend spontaneously soon after birth from those that will remain suprascrotal. Also, the natural course of development of testicles that are suprascrotal at birth but descend during the first 6 months of life must be established. CONCLUSIONS The current study shows that early surgical treatment at age 9 months resulted in partial catch-up of testicular growth until age 4 years. This was not the case if surgery was delayed until age 3 years, clearly indicating that early surgery has a beneficial effect on testicular growth. Since testicular volume is an approximate measure of spermatogenic activity, this gives hope that early orchiopexy may improve future spermatogenesis. ACKNOWLEDGMENTS Pia Kjellholm provided assistance and Magnus Backheden provided statistical support. REFERENCES 1.
2.
3.
4. 5.
6.
7.
8.
9. 10.
11.
12.
Berkowitz GS, Lapinski RH, Dolgin SE, Gazella JG, Bodian CA and Holzman IR: Prevalence and natural history of cryptorchidism. Pediatrics 1993; 92: 44. Boisen KA, Kaleva M, Main KM, Virtanen H, Haavisto AM, Schmidt IM et al: High and increasing prevalence of cryptorchidism in Denmark. Ugeskr Laeger 2004; 22: 4372. Lee PA and Coughlin MT: Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data. Horm Res 2001; 55: 28. Lee PA and Coughlin MT: The single testis: paternity after presentation as unilateral cryptorchidism. J Urol 2002; 168: 1680. Engeler DS, Hösli PO, John H, Bannwart F, Sulser T, Amin MB et al: Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome. Urology 2000; 56: 144. Ong C, Hasthorpe S and Hutson JM: Germ cell development in the descended and cryptorchid testis and the effects of hormonal manipulation. Pediatr Surg Int 2005; 21: 240. Ritzen EM, Bergh A, Bjerknes R, Christiansen P, Cortes D, Haugen SE et al: Nordic consensus on treatment of undescended testes. Acta Paediatr 2007; 96: 638. Hadziselimovic F and Herzog B: The importance of both an early orchidopexy and germ cell maturation for fertility. Lancet 2001; 358: 1156. Cortes D, Petersen BL and Thorup J: Testicular histology in cryptorchid boys—aspects of fertility. Unpublished data. Takihara H, Cosentino MJ, Sakatoku J and Cockett AT: Significance of testicular size measurement in andrology: II. Correlation of testicular size with testicular function. J Urol 1987; 137: 416. Lenz S, Giwercman A, Elsborg A, Cohr KH, Jelnes JE, Carlsen E et al: Ultrasonic testicular texture and size in 444 men from the general population: correlation to semen quality. Eur Urol 1993; 24: 231. Noh PH, Cooper CS, Snyder HM, Zderic SA, Canning DA and Huff DS: Testicular volume does not predict germ cell count in patients with cryptorchidism. J Urol 2000; 163: 593.
SURGICAL TREATMENT OF UNILATERALLY UNDESCENDED TESTES 13.
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Diamond DA, Paltiel HJ, DiCanzio J, Zurakowski D, Bauer SB, Atala A et al: Comparative assessment of pediatric testicular volume: orchidometer versus ultrasound. J Urol 2000; 164: 111. Main KM, Toppari J, Suomi AM, Kaleva M, Chellakoty M, Schimidt IM et al: Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys. J Clin Endocrinol Metab 2006; 91: 2732. Kollin C, Hesser U, Ritzén M and 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. Hedinger C: Histological data in cryptorchidism. In: Pediatric Adolescent Endocrinology: Cryptorchidism: Diagnosis and Treatment. Basel: Karger 1979; vol 6, pp 3–13. Puri P and Sparnon A: Relationship of primary site of testis to final testicular size in cryptorchid patients. Br J Urol 1990; 66: 208. Cendron M, Huff DS, Keating MA, Snyder HM 3rd and Duckett JW: Anatomical, morphological and volumetric analysis: a review of 759 cases of testicular maldescent. J Urol 1993; 149: 570. Bedford JM: Effects of elevated temperatures on the epididymis and testis: experimental studies. Adv Exp Med Biol 1991; 286: 19. Fenig DM, Snyder HM, Wu H, Canning DA and Huff DS: The histopathology of iatrogenic cryptorchid testis: an insight into etiology. J Urol 2001; 165: 1258.
EDITORIAL COMMENT This prospective, randomized trial addresses an important question of the timing of orchiopexy (age 9 months vs 3 years). The authors conclude that early orchiopexy resulted in partial catch-up of testicular growth compared to the contralateral descended mate. The largest increase in growth for the early group occurred by 2 years at 3 months postoperatively. To fully compare the early and late surgery groups the same followup should have been used. Although the prepubertal testis is often viewed as quiescent, some
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groups have reported a small, second postnatal surge of luteinizing hormone and resultant testosterone linked with the eventual appearance of primary spermatocytes around age 5 years,1,2 although others did not see this surge.3 It would be interesting to continue testicular volume measurements through this period to see whether any further changes are evident. While the authors state that testicular volume may be used as a surrogate for a measure of spermatogenesis, this association is most commonly seen in adulthood. In children Noh et al found that, although the generalizing estimating equation demonstrated a direct correlation between testicular volume and germ cell count, individual germ cell count/ volume measures varied widely within the CIs (reference 12 in article). They concluded that testis volumes at orchiopexy could not be used to reliably predict individual germ cell histology. Further studies may elucidate whether early orchiopexy in a period of testis plasticity is able to evoke changes in histology that will allow improved spermatogenesis and paternity in adulthood. Thomas F. Kolon Department of Urology Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 1.
Waaler PE, Thorsen T, Stoa KF and Aarskog D: Studies in normal male puberty. Acta Paediatr Scand, suppl., 1974; 249: 1. 2. Huff DS, Fenig DM, Canning DA, Carr MC, Zderic SA and Snyder HM III: Abnormal germ cell development in cryptorchidism. Horm Res 2001; 55: 11. 3. Chada M, Prusa R, Bronsky J, Kotaska K, Sidlova K, Pechova M et al: Inhibin B, follicle stimulating hormone, luteinizing hormone and testosterone during childhood and puberty in males: changes in serum concentrations in relation to age and stage of puberty. Physiol Res 2003; 52: 45.
Purpose: We compared the growth of congenital, unilaterally undescended testes following orchiopexy at age 9 months or 3 years. Materials and Methods: Patients were randomized to surgery at age 9 months (72) or 3 years (83). Testicular volume was measured by ultrasonography at ages 6, 12, 24, 39 and 48 months. Results: Orchiopexy at age 9 months resulted in an increase in testicular volume at subsequent measurements at ages 2, 3 and 4 years compared to the volume at 6 months (p ⬍0.001). In contrast, no significant growth was noted in the group treated at age 3 years. The improved testicular growth after early orchiopexy was also demonstrated by a gradual increase in the ratio of the previously retained testis and the scrotal testis in individual boys from 6 months to 4 years (0.68 to 0.81, p ⬍0.001). For the late treatment group a significant decrease in this ratio was noted during the same period (0.68 to 0.56, p ⬍0.01). Conclusions: Surgical treatment at 9 months resulted in partial catch-up of testicular growth until at least age 4 years compared to surgery at 3 years, clearly indicating that early surgery has a beneficial effect on testicular growth. Since testicular volume is an approximate indirect measure of spermatogenic activity, this gives hope that orchiopexy at this age may improve future spermatogenesis. Key Words: testis; cryptorchidism; infertility, male; spermatozoa; abnormalities
ndescended testes is the most common congenital anomaly in boys.1 The prevalence in full-term newborns (birth weight 2,500 gm or greater) is approximately 3%, decreasing by spontaneous descent to 1% to 2% by age 6 months. The incidence seems to be increasing in Denmark, suggesting an environmental influences on genital development.2 Unilateral cryptorchidism accounts for about 85% of all cases.1 Failure of bilateral testicular descent results in severely impaired spermatogenesis. If untreated, this results in infertility in adulthood.3 In agreement with these studies a decreased paternity rate has been observed after surgically treated bilateral cryptorchidism but not after unilateral cryptorchidism.4 Orchiopexy for bilateral cryptorchidism leads to a higher normal sperm count if surgery was performed before age 3 years compared to surgery after age 4 years.5 Therefore, it is generally accepted that retained testes should be brought into the scrotum at some time during early childhood. The means of accomplishing this are hormonal or surgical treatment. Two modes of hormone treatment have been suggested but each has been of doubtful efficacy and safety.
U
Study received approval from the Committee for Ethics in Medical Research at Karolinska Institutet. Supported by Stiftelsen Frimurare Barnhuset, Sällskapet Barnavård, Kronprinsessans Lovisas och Axel Tielmans fond för barnsjukvård and Sven Jerrings Fond. * Correspondence: Department of Woman and Child Health, Karolinska Institutet, Pediatric Surgery (Q3:03), Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden (telephone: ⫹46 8 51777714; FAX: ⫹ 46 8 51777715; e-mail: [email protected]).
0022-5347/07/1784-1589/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
Several groups have disputed the effectiveness of gonadotropin releasing hormone or human chorionic gonadotropin treatment.6 Therefore, surgical positioning of the retained testes into the scrotum has gained renewed popularity.7 However, the optimal age for surgical treatment remains controversial. Based on histopathological studies it was suggested that surgery should be performed within the first 2 years of life.8,9 To our knowledge there are no published, prospective studies that randomized boys with undescended testes to surgery at different ages with postoperative followup of testicular growth and function. Since the final goal of treatment is to achieve normal adult spermatogenesis, repeat testicular biopsies would seem to be the optimal way to monitor treatment success. However, this would not be ethically acceptable. Instead, repeat measurements of testicular volume may serve as a surrogate since there is a good correlation between the spermatogenic activity of a testicle, and its volume in adults10,11 and in prepubertal children.12 Therefore, we focused on testicular growth before and after orchiopexy at age 9 months or 3 years a followup to age 4 years. Ultrasonography is a reliable method for determining testicular volume13 with precision and reproducibility also during the first years of life.14 Thus, an accurate determination of the volume of the retained and scrotal testes using ultrasonography before and repeatedly after treatment seems to be acceptable as an early marker of the success of treatment. This report is the followup of a previous study in which patients with and without orchiopexy at age 9 months were followed until age 24 months.15 Further details of study
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Vol. 178, 1589-1593, October 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.03.173
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SURGICAL TREATMENT OF UNILATERALLY UNDESCENDED TESTES
design, surgical procedure, definitions and methods can be found in the previous publication. PATIENTS AND METHODS This study began in 1998 at the Astrid Lindgren Children’s Hospital, Karolinska University Hospital. A total of 164 boys with unilateral palpable undescended testis were included in the study, of whom 117 were recruited at ages 0 to 3 weeks and 47 were referred later and included at age 6 months. According to neonatal records the latter boys had unilaterally palpable undescended testes also at birth. At age 6 months the boys were randomized to surgery at age 9 months (72) or 3 years (83). Nine boys who were included at birth withdrew before age 6 months due to lack of parental compliance and they were consequently not randomized. Some patients did not undergo all ultrasound examinations because they missed appointments, were ill or came too late for ultrasonography. Clinical and ultrasound examinations were used to define the position and volume of the 2 testicles at ages 0 to 3 weeks, 2 months (no ultrasonography), 6 months, and 12, 24, 36 and 39 months in the late treatment group, and 48 and 60 months at all time points ⫾ 2 weeks. The number of ultrasound examinations varied somewhat at different time points, although patients remained in the study. Blood samples for hormone measurements were collected at each visit and at surgery biopsy was done for histological evaluation (data not shown). One pediatric surgeon (CK) performed more than 95% of the clinical examinations and surgical procedures. Inclusion criteria were congenital unilateral palpable undescended testis at ages 0 to 3 weeks or at 6 months. Exclusion criteria were spontaneous descent, recognized syndromes, other birth defects or other pathological conditions afflicting the external genitalia, prematurity (less than 37 weeks of gestation) and prior groin surgery. Definition of Palpable Undescended Testes All testes that could not be brought down into the scrotum at clinical examination were included. If a testis in a suprascrotal position could be pulled down to the upper part of scrotum but did not remain there after about 30 seconds of traction (after the 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 it could be pulled down to the lower part of the scrotal position, it was defined as a retractile testis and not included. Ultrasound was performed with high resolution scanners. Testicular volume was calculated using the approximation for a prolapsed ellipsoid, V ⫽ /6 ⫻ length ⫻ width ⫻ height. The majority of procedures were performed by 1 pediatric radiologist (UH). Examiners were blinded to previous results and preliminary data but obviously the scars of orchiopexy were clearly visible. At the 4-year ultrasound this was not a problem since a 1-year-old scar could not be distinguished from a 3-year-old scar. All parts of this study were approved by the Committee for Ethics in Medical Research at the Karolinska Institutet. Statistical Methods The measured volume of the testicles of 164 boys was analyzed with a generalized linear model for longitudinal data. Due to skewed distribution of residuals the logarithm of testicular volumes was used for calculations. Missing values were assumed to be missing at random. Due to the number of missing values data were analyzed with PROC MIXED in SAS®. RESULTS Testicular volumes previously reported up to age 2 years15 are included in the total numbers to show the full development from ages birth to 4 years. Testicular size was determined in the retained and the scrotal testis in each patient. Development of the Scrotal and Retained Testes From Birth to 6 Months Between ages 0 to 3 weeks and 6 months median volume of the normally descended testis increased from 0.30 to 0.51 ml (p ⬍0.001, see table and fig. 1). The retained testis increased from 0.25 to 0.35 ml (p ⬍0.001, see table and fig. 2). There was a significant difference in median volume between the scrotal and retained testes at ages 0 to 3 weeks and 6 months (each p ⬍0.001). Thus, during the first 6 months postnatally the volume of the descended testis increased by 70%, while the increase in the retained testis was only 40%.
Volume at various ages of retained and scrotal testes, and ratio between them in early and late treated groups Undescended Testis
Descended Testis
Undescended/Descended
Age group
No. Testes
Median Vol (ml)
No. Testes
Median Vol (ml)
No. Testes
Median
0–3 Wks 6 Mos 12 Mos: Early surgery Late surgery 24 Mos: Early surgery Late surgery 36 Mos: Early surgery Late surgery 48 Mos: Early surgery Late surgery
110 139
0.25 0.35
112 144
0.30 0.51
110 139
0.84 0.68
67 72
0.38 0.33
67 72
0.51 0.51
67 72
0.74 0.66
53 63
0.42 0.33
54 66
0.56 0.54
53 63
0.73 0.60
43 44
0.49 0.38
44 45
0.59 0.58
43 44
0.86 0.64
33 44
0.50 0.38
33 44
0.65 0.64
33 44
0.80 0.56
Orchiopexy was performed at ages 9 months and 3 years.
SURGICAL TREATMENT OF UNILATERALLY UNDESCENDED TESTES
FIG. 1. Development of volume of initially retained testes in boys with palpable unilaterally undescended testes from ages 0 to 3 weeks (w) to 4 years (y). At age 6 months (mo) all boys were randomized to orchiopexy at 9 months (72) or 3 years (83). At ages 2, 3 and 4 years there was significant difference in median volume of initially retained testes between early and late treated groups (p ⬍0.001). Curves show median and 95% CI. Values indicate number of testes.
Further Growth of the Scrotal Testes From 6 Months to 4 Years Between 6 months and 4 years an increase in the median volume of the scrotal testes was noted (p ⬍0.001, see table and fig. 1). There were no significant differences in scrotal testis volume between the 2 groups at any age. Further Growth of The Retained Testes From 6 Months to 4 Years and the Influence of Orchiopexy at 9 Months or 3 Years Orchiopexy at age 9 months resulted in an increase in median testicular volume from 0.35 ml at 6 months to 0.42 ml at 2 years, 0.49 at 3 years and 0.50 ml at 4 years (p ⬍0.001, see table and fig. 1). Thus, orchiopexy was followed by significant partial catch-up growth. In contrast, during the
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FIG. 3. Development of volume of initially retained testes in boys with palpable unilaterally undescended testes from ages 0 to 3 weeks (w) to 4 years (y). At age 6 months (mo) all boys were randomized to orchiopexy at 9 months (72) or 3 years (83). In early treated group there was increase in median ratio from ages 6 months to 3 and 4 years (p ⬍0.001). At ages 2, 3 and 4 years there was significant difference in this ratio between early and late treated groups, again showing partial catch-up growth of early treated testis (p ⬍0.001). Curves show median and 95% CI. Values indicate number of ultrasound examinations.
same period there was no significant growth of the retained testes before or after surgery in the group randomized to orchiopexy at 3 years. At ages 2, 3 and 4 years there were significant differences in median volume between testes that were surgically treated at 9 months compared to the group with treatment at age 3 years (p ⬍0.001, see table). The volume of the initially retained testis in each group still had not reached the size of its scrotal counterpart on any measurements at age 2, 3 or 4 years. Retained-to-Scrotal Testis Ratio The ratio of the volume of the undescended testis and its contralateral scrotal counterpart provided a direct comparison of the 2 testes in individual boys. Thus, it is an index of the degree of growth deficit of the retained testis. In the early treatment group operated at 9 months there was an increase in the median ratio from 0.68 at 6 months to 0.81 at 4 years (p ⬍0.001). In contrast, a decrease in the median ratio was noted in the late treatment group (at 3 years) from 0.68 at 6 months to 0.56 at 4 years (p ⬍0.001, see table and fig. 3). At ages 2, 3 and 4 years there were significant differences in this ratio between the early and late treatment groups, again demonstrating the partial catch-up growth of early treated testes (p ⬍0.001). DISCUSSION
FIG. 2. Development of volume of initially retained testes in boys with palpable unilaterally undescended testes from ages 0 to 3 weeks (w) to 4 years (y). At age 6 months (mo) all boys were randomized to orchiopexy at 9 months (72) or 3 years (83). There was no significant difference in scrotal testicular volume between early and late treated groups at any age. Curves show median and 95% CI. Values indicate number of testes.
There is a general consensus that cryptorchidism should be treated in early childhood to achieve normal spermatogenesis and normal fertility. In the search for improvements interest has focused on age at treatment. In the classic histopathological studies of Hedinger the number of spermatogonia per tubular cross-section was decreased in undescended testes from age 2 years and thereafter compared to a normal population.16 This was later confirmed by others. However, this proves neither that treatment at age 1 year
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SURGICAL TREATMENT OF UNILATERALLY UNDESCENDED TESTES
would save normal spermatogenesis nor that treatment at a later age would lead to a worse result in adulthood. Thus, prospective, randomized, controlled studies of the effect of orchiopexy in infancy compared to later surgery are needed. In the current study boys were randomized to surgical treatment at age 9 months or 3 years. A way of assessing the effect of surgery on undescended testes during childhood would be to follow testicular growth. In normal boys testicular volume almost doubles during the first 3 months of life with little or no further increase between ages 3 and 18 months.14 Also, during the following years testicular growth is slow, as demonstrated in the current study by the development of the scrotal testes during the first 4 years of life (see table and fig. 2), showing slow, statistically nonsignificant growth during the second and fourth years of life. Thus, comparing the volume of the previously retained testes during the first year after surgery at age 9 or 36 months should be a way to compare the effectiveness of treatment at these 2 ages. Also, a comparison of the ratio between the retained and the scrotal testis in the 2 groups can be a good measurement of therapeutic success. To our knowledge this prospective, randomized study shows for the first time that early orchiopexy at age 9 months results in significant catch-up growth of the initially retained testes up to age 4 years, which contrasts with the complete absence of growth of testes that are still undescended until age 3 years. The growth of these latter testes could not be salvaged by surgery at 3 years. No resumed growth was noted until the end of the current followup at age 4 years. Also, the ratio between the previously retained testis and its scrotal counterpart showed a significant increase following early surgery, while in the late treated group this ratio showed a significant decrease even after surgery. These results strongly suggest that surgery at age 9 months rather than 3 years is beneficial for testicular growth. Our results are consistent with those in previous studies showing that the volume of the retained testes is usually less than volume of scrotal testes with the difference persisting into adulthood.17,18 However, those studies were not prospective with measurements of testicular size at birth, nor did they assess testicular growth during the first months of life, a period when the testes show more activity than at any other time before puberty. We found a significant difference in volume between scrotal and retained testes at the first measurement at age 0 to 3 weeks. This suggests that prenatal factors have a role in impaired testicular growth. However, in the first report of this study it was shown that retained testes that at birth were close to equal in volume with the contralateral scrotal testis showing a significant difference in volume at 6 months.15 This suggests that impaired growth of the retained testis was not only due to prenatal factors. Increased temperature was suggested to be the most probable causative factor.19 Also, a biopsy study of iatrogenic cryptorchidism after hernia repair showed that these testes have a decreased number of germ cells per tubular cross-section as time in a suprascrotal position increases, indicating that these testes undergo secondary adverse changes and accumulated time in the suprascrotal environment has an important role.20 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 to whether surgery was performed at a younger age.9
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 damage to undescended testes. However, before beginning such a study methods must be developed to distinguish testes that will descend spontaneously soon after birth from those that will remain suprascrotal. Also, the natural course of development of testicles that are suprascrotal at birth but descend during the first 6 months of life must be established. CONCLUSIONS The current study shows that early surgical treatment at age 9 months resulted in partial catch-up of testicular growth until age 4 years. This was not the case if surgery was delayed until age 3 years, clearly indicating that early surgery has a beneficial effect on testicular growth. Since testicular volume is an approximate measure of spermatogenic activity, this gives hope that early orchiopexy may improve future spermatogenesis. ACKNOWLEDGMENTS Pia Kjellholm provided assistance and Magnus Backheden provided statistical support. REFERENCES 1.
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Berkowitz GS, Lapinski RH, Dolgin SE, Gazella JG, Bodian CA and Holzman IR: Prevalence and natural history of cryptorchidism. Pediatrics 1993; 92: 44. Boisen KA, Kaleva M, Main KM, Virtanen H, Haavisto AM, Schmidt IM et al: High and increasing prevalence of cryptorchidism in Denmark. Ugeskr Laeger 2004; 22: 4372. Lee PA and Coughlin MT: Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data. Horm Res 2001; 55: 28. Lee PA and Coughlin MT: The single testis: paternity after presentation as unilateral cryptorchidism. J Urol 2002; 168: 1680. Engeler DS, Hösli PO, John H, Bannwart F, Sulser T, Amin MB et al: Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome. Urology 2000; 56: 144. Ong C, Hasthorpe S and Hutson JM: Germ cell development in the descended and cryptorchid testis and the effects of hormonal manipulation. Pediatr Surg Int 2005; 21: 240. Ritzen EM, Bergh A, Bjerknes R, Christiansen P, Cortes D, Haugen SE et al: Nordic consensus on treatment of undescended testes. Acta Paediatr 2007; 96: 638. Hadziselimovic F and Herzog B: The importance of both an early orchidopexy and germ cell maturation for fertility. Lancet 2001; 358: 1156. Cortes D, Petersen BL and Thorup J: Testicular histology in cryptorchid boys—aspects of fertility. Unpublished data. Takihara H, Cosentino MJ, Sakatoku J and Cockett AT: Significance of testicular size measurement in andrology: II. Correlation of testicular size with testicular function. J Urol 1987; 137: 416. Lenz S, Giwercman A, Elsborg A, Cohr KH, Jelnes JE, Carlsen E et al: Ultrasonic testicular texture and size in 444 men from the general population: correlation to semen quality. Eur Urol 1993; 24: 231. Noh PH, Cooper CS, Snyder HM, Zderic SA, Canning DA and Huff DS: Testicular volume does not predict germ cell count in patients with cryptorchidism. J Urol 2000; 163: 593.
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Diamond DA, Paltiel HJ, DiCanzio J, Zurakowski D, Bauer SB, Atala A et al: Comparative assessment of pediatric testicular volume: orchidometer versus ultrasound. J Urol 2000; 164: 111. Main KM, Toppari J, Suomi AM, Kaleva M, Chellakoty M, Schimidt IM et al: Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys. J Clin Endocrinol Metab 2006; 91: 2732. Kollin C, Hesser U, Ritzén M and 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. Hedinger C: Histological data in cryptorchidism. In: Pediatric Adolescent Endocrinology: Cryptorchidism: Diagnosis and Treatment. Basel: Karger 1979; vol 6, pp 3–13. Puri P and Sparnon A: Relationship of primary site of testis to final testicular size in cryptorchid patients. Br J Urol 1990; 66: 208. Cendron M, Huff DS, Keating MA, Snyder HM 3rd and Duckett JW: Anatomical, morphological and volumetric analysis: a review of 759 cases of testicular maldescent. J Urol 1993; 149: 570. Bedford JM: Effects of elevated temperatures on the epididymis and testis: experimental studies. Adv Exp Med Biol 1991; 286: 19. Fenig DM, Snyder HM, Wu H, Canning DA and Huff DS: The histopathology of iatrogenic cryptorchid testis: an insight into etiology. J Urol 2001; 165: 1258.
EDITORIAL COMMENT This prospective, randomized trial addresses an important question of the timing of orchiopexy (age 9 months vs 3 years). The authors conclude that early orchiopexy resulted in partial catch-up of testicular growth compared to the contralateral descended mate. The largest increase in growth for the early group occurred by 2 years at 3 months postoperatively. To fully compare the early and late surgery groups the same followup should have been used. Although the prepubertal testis is often viewed as quiescent, some
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groups have reported a small, second postnatal surge of luteinizing hormone and resultant testosterone linked with the eventual appearance of primary spermatocytes around age 5 years,1,2 although others did not see this surge.3 It would be interesting to continue testicular volume measurements through this period to see whether any further changes are evident. While the authors state that testicular volume may be used as a surrogate for a measure of spermatogenesis, this association is most commonly seen in adulthood. In children Noh et al found that, although the generalizing estimating equation demonstrated a direct correlation between testicular volume and germ cell count, individual germ cell count/ volume measures varied widely within the CIs (reference 12 in article). They concluded that testis volumes at orchiopexy could not be used to reliably predict individual germ cell histology. Further studies may elucidate whether early orchiopexy in a period of testis plasticity is able to evoke changes in histology that will allow improved spermatogenesis and paternity in adulthood. Thomas F. Kolon Department of Urology Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 1.
Waaler PE, Thorsen T, Stoa KF and Aarskog D: Studies in normal male puberty. Acta Paediatr Scand, suppl., 1974; 249: 1. 2. Huff DS, Fenig DM, Canning DA, Carr MC, Zderic SA and Snyder HM III: Abnormal germ cell development in cryptorchidism. Horm Res 2001; 55: 11. 3. Chada M, Prusa R, Bronsky J, Kotaska K, Sidlova K, Pechova M et al: Inhibin B, follicle stimulating hormone, luteinizing hormone and testosterone during childhood and puberty in males: changes in serum concentrations in relation to age and stage of puberty. Physiol Res 2003; 52: 45.