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In cryptorchidism, germ cell development failure presents from infancy and may be reflected by altered hormonal levels produced by Sertoli cells. Our object was to assess for associations between serum hormone levels and testicular histopathology in cryptorchidism with an infertility risk according to the pretreatment undescended testicular positions.Prepubertal cryptorchid boys aged 7-91 (median 20) months who underwent orchidopexy between 2014 and 2019 were included (122 unilateral [median 19 months {range 7-91}], 23 bilateral [24 months {11-81}]). We evaluated the pretreatment testicular position and size; serum hormone levels; and the mean number of germ cells per tubule transverse section (G/T). We also performed a subgroup analysis of boys aged ≤24 months at orchidopexy.Serum inhibin B levels and G/T were significantly lower in bilateral than in unilateral cryptorchid boys (median 96 [range 46-197] pg/ml vs 125 [21-354] pg/ml, p=0.026; 0.20 [0-2.59] vs 0.65 [0-4.55], p0.001, respectively). Inhibin B/follicle-stimulating hormones (FSH) and anti-Müllerian hormone (AMH)/FSH ratios were positively correlated with G/T in bilateral cryptorchid boys aged ≤24 months (12, p=0.008 and p=0.019, respectively). Low inhibin B/FSH and AMH/FSH ratios and high FSH were predictors of impaired G/T as per receiver operating characteristic curves (p=0.019, p=0.004 and p=0.004, respectively), whereas in unilateral cryptorchid boys aged ≤24 months, serum hormone levels and G/T did not differ with the pretreatment testicular positions.In bilateral cryptorchid boys aged ≤24 months at orchidopexy, low inhibin B/FSH and AMH/FSH ratios may reflect impaired G/T and future infertility risk.

We performed a retrospective, single-institution study to characterize the pathological findings of testis tissue specimens from older boys and adolescents with cryptorchidism.With institutional review board approval, pathology reports were obtained for testicular specimens from patients age 10 years or older at a pediatric hospital from 1994 to 2016. Reports were excluded if they lacked clinical records, lacked testicular parenchyma, were from a descended testis or were from a patient with differences of sexual development. Variables of interest included age, testis location, procedure and pathological findings. Presence of malignancy among intra-abdominal versus extra-abdominal undescended testes was compared using Fisher's Exact Test.Seventy-one patients met inclusion criteria. The median age was 15.3 years (range 10.1-27.7). None had a history of testicular malignancy. Forty-five unilateral orchiectomies, 22 unilateral orchiopexies with biopsy and 4 bilateral procedures were performed. Seventeen testes (22.7%) were intra-abdominal, 42 (56.0%) were in the inguinal canal, 9 (12.0%) were at the external inguinal ring, 3 (4.0%) were in the superficial inguinal pouch and 4 (5.3%) were in the scrotum. Malignancy was detected in 2/71 patients (2.8%). By location, 2/16 patients (12.5%) with intra-abdominal testis and 0/55 patients (0%) with extra-abdominal testis demonstrated malignancy (p=0.048).Among males with cryptorchidism ages 10 years and older without differences of sexual development, 2/16 patients with intra-abdominal testis and 0/55 patients with extra-abdominal testis demonstrated malignancy. In older boys and adolescents, orchiectomy or biopsy is indicated for intra-abdominal testes but may not be necessary for extra-abdominal undescended testes.

We identified the incidence of acquired cryptorchidism among patients with proximal and mid shaft hypospadias, predictors of acquired cryptorchidism, and the prevalence of testis-epididymis nonfusion with ascended testes. We hypothesized that proximal hypospadias would be associated with higher incidence of acquired cryptorchidism than mid shaft hypospadias, and that ascended testes would exhibit increased prevalence of testis-epididymis nonfusion similar to anatomical findings in an undescended testis.A retrospective cohort study of patients who underwent primary proximal and mid shaft hypospadias repair from 2010 to 2016 was conducted. Clinical and operative notes were reviewed. Patients with congenitally undescended testes or differences of sex development were excluded.A total of 175 patients were identified. Those with proximal hypospadias (14/104, 13%) were more likely than those with mid shaft hypospadias (1/71, 1%) to develop acquired cryptorchidism (p=0.04). Among proximal hypospadias patients, increased risk of acquired cryptorchidism was associated with pre-term birth (p0.01) and penoscrotal transposition (p=0.01) but not with testis position on initial examination (p0.99). In the 14 proximal hypospadias patients with acquired cryptorchidism, 21 ascended testes underwent orchiopexy. Operative notes adequately described testis-epididymis anatomy for 8/21 ascended testes. Testis-epididymis nonfusion was described in 6/8 ascended testes.Risk of acquired cryptorchidism is increased among patients with proximal hypospadias. Operative notes revealed a high rate of epididymal nonfusion with ascended testes, suggesting these testes morphologically resemble undescended testes. Close followup of testis position is needed in these patients, and the threshold to perform orchiopexy may need to be lower in select patients.

Ascending testes have been documented to be descended in the scrotum within the first year of life and then reascended. The aim of this study was to investigate to what extent the fertility potential was impaired in boys with such testes compared to the fertility potential of boys with late referral congenital cryptorchidism.A total of 153 consecutive boys underwent bilateral orchiopexy at age 2 to 7 years (median 3.9) between 2011 and 2018. Of the patients 67 were diagnosed with bilateral ascended testes and 86 with late referral bilateral congenital cryptorchidism. We assessed serum levels of inhibin B and gonadotropins and histological parameters, number of germ cells per tubule cross-section and number of type A dark (Ad) spermatogonia per tubule cross-section. All values were compared to our normal material.Number of germ cells per tubule cross-section of boys with ascended testes (median 0.50, range 0 to 2.29) was not significantly higher compared to boys with congenital cryptorchidism (median 0.37, range 0 to 2.57; p=0.11). Mean number of germ cells per tubule cross-section was below normal range in 40 boys with ascending testes (60%) vs 57 boys with late referral congenital cryptorchidism (66%, p=0.40). Biopsies absent of Ad spermatogonia were noted in 31% of boys with ascending testes (21 of 67) vs 34% of boys with congenital cryptorchidism (29 of 86, p=0.76). Serum levels of inhibin B and gonadotropins did not differ between the 2 groups.The fertility potential of boys with bilateral ascended testes was impaired to almost the same level as that of boys with bilateral congenital cryptorchidism and should therefore be surgically corrected as soon as the diagnosis of ascended testes is settled.

Gubernaculum sparing laparoscopic orchiopexy, which involves anatomical delivery of the testis through the internal inguinal ring, has been proposed as an alternative to conventional laparoscopic Fowler-Stephens orchiopexy, maximizing collateral blood supply and potentially decreasing atrophy rates. We compared the 2 techniques to test this hypothesis.The primary (dependent) outcome of the study was rate of testicular atrophy, which was defined as palpation of a nubbin or inability to palpate a testis (complete atrophy) on postoperative physical examination at 3 and 12 months. Doppler ultrasound was obtained routinely to further confirm the diagnosis of testicular atrophy. Independent variables that were captured were age at surgery, type of procedure (conventional laparoscopic Fowler-Stephens orchiopexy vs gubernaculum sparing laparoscopic orchiopexy), surgical approach (single vs 2-stage), location of intra-abdominal testis (high vs low) and patency of the internal inguinal ring.Mean ± SD age at surgery was 25.7 ± 13.3 months (median 22). Laparoscopy was carried out for nonpalpable testes and revealed vanishing intra-abdominal testes in 120 cases (29%), peeping testes in 80 (19%) and intra-abdominal testes in 212 (51%), with 104 being low and 108 being high in the abdomen. A single stage procedure was performed in 44 cases (21%) and a 2-stage procedure in 168 (79%). Based on surgeon preference, conventional laparoscopic Fowler-Stephens orchiopexy was undertaken in 46 patients (22%) and gubernaculum sparing laparoscopic orchiopexy in 166 (78%). Overall testicular atrophy rate was 6.6% (14 of 212 cases). Atrophy was observed in 13 of 46 testes after conventional laparoscopic Fowler-Stephens orchiopexy and 1 of 166 following gubernaculum sparing laparoscopic orchiopexy (28.3% vs 0.6%, p0.01).Gubernaculum sparing laparoscopic orchiopexy is a feasible alternative to conventional laparoscopic Fowler-Stephens orchiopexy. Our findings suggest that preservation of additional vascular supply to the testis (cremasteric vessels and deferential artery) may translate into improved testicular survival rates following laparoscopic orchiopexy.

We performed low scrotal approach orchiopexy in patients with prescrotal cryptorchidism. The processus vaginalis was not ligated if it was not widely patent. We retrospectively evaluated the long-term outcomes of low scrotal approach orchiopexy without processus vaginalis ligation.A total of 137 patients (227 testes) were diagnosed with prescrotal cryptorchidism between October 2009 and April 2014. All patients underwent low scrotal approach orchiopexy. Mean age at surgery was 34.9 months. The processus vaginalis was deemed to be not widely patent when a sound could not be passed into the abdominal cavity through the internal inguinal ring, and the processus vaginalis was not ligated in such cases.Intraoperative findings revealed that the processus vaginalis was widely patent in 10 testes and was not widely patent in 217. A widely patent processus vaginalis was closed via scrotal approach in 5 testes, while an inguinal approach was necessary in 5. Median followup was 44 months (range 20 to 73). Postoperative complications included reascending testis in 1 case where an inguinal approach was necessary. No patient manifested testicular atrophy or inguinal hernia.Low scrotal approach orchiopexy is a useful and safe procedure for treating patients with prescrotal cryptorchidism. Ligation is unnecessary when the processus vaginalis is not widely patent.

Purpose: Undescended testis leads to infertility and malignancy resulting from aberrant germ cell development. Androgens are proposed to control early germ cell development during the transient postnatal surge of gonadotropins and androgen, known as mini-puberty. We assessed the effect of androgen receptor on perinatal germ cell development in mice.Materials and Methods: Testes from androgen receptor knockout mice and wildtype littermates (3 to 4 per group) were collected at embryonic day 17 and postnatal days 0 (birth), 2, 4, 6, 8 and 10 for immunohistochemical analysis. Antibodies against mouse VASA homologue (germ cell marker), antimullerian hormone (Sertoli cell marker), Ki67 (proliferating cell marker) and DAPI (nuclei) were used and visualized by confocal microscopy. Number of germ cells per tubule, germ cells on the tubular basement membrane and Sertoli cells per tubule, and percentage of proliferating germ cells (Ki67(+)) per tubule and germ cells (Ki67(+)) on the basement membrane on confocal images were counted using Image J, version 1.44 (http://imagej.nih.gov/ij/). Data were analyzed using nonparametric one-way ANOVA with GraphPad Prism (R) 5.02 software.Results: In wild-type and androgen receptor knockout testes germ cells per tubule decreased from embryonic day 17 to postnatal day 2, then increased normally. Number of mouse VASA homologue positive germ cells per tubule and germ cells on the basement membrane were similar in androgen receptor knockout and wild-type testes (p > 0.05) at each age, and percentages of proliferating germ cells (Ki67(+)) per tubule and proliferating germ cells on the basement membrane were similar at each age (p > 0.05).Conclusions: Androgen receptors are not required for gonocyte migration from the center of the testicular tubules to the basement membrane and transformation into spermatogonia stem cells up to day 10 in androgen receptor knockout mice. Identifying nonandrogenic factors might improve the fertility potential of boys with undescended testis who are undergoing orchiopexy.

We evaluate the histopathological features of uncorrected undescended testis presenting at a late postpubertal age.The study included 51 men (age 20 to 24 years) diagnosed with inguinal unilateral undescended testis found on routine examination for military recruits. None was evaluated or treated for undescended testis previously. All of the men had a normal contralateral testis and no other observed phenotypic alterations, and all had undergone unilateral orchiectomy. The surgical specimens were first examined histologically, and sections were additionally examined with immunohistochemical methods using antibodies against CD117 and OCT3/4 proteins to verify the presence of intratubular germ cell neoplasia.Histopathology revealed the presence of germ cells at different maturation levels in 26 of 51 (51%) cases. There were 28 cases (55%) with different degrees of basal membrane thickening. A decrease in seminiferous tubule diameter was observed in 23 (45%) patients. Six patients (12%) had dystrophic calcification and 12 (24%) had Leydig cell hyperplasia. Although morphological evaluation did not show intratubular germ cell neoplasia in any patients, 1 with germ cells had positivity for OCT3/4 and CD117 staining. Therefore, 1 case out of 51 had diagnosed intratubular germ cell neoplasia.There was a wide range of histopathological changes in undescended testis. Nearly half the patients may still have significant germ cell activity at a variety of maturation levels. The incidence of intratubular germ cell neoplasia was 2% in this group. Intratubular germ cell neoplasia may be overlooked with hematoxylin and eosin staining so immunohistochemical study should be added for evaluation.

The incidence of intersex states has been reported to be 27% to 100% in patients with hypospadias and cryptorchidism, and routinely determining karyotypes has been recommended. This incidence seems much higher than in our experience. We reviewed the records of patients with hypospadias and/or chordee plus cryptorchidism as well as those referred with ambiguous genitalia to determine whether these findings were associated with a high incidence of chromosomal abnormalities and whether they warrant routine karyotype screening.We reviewed the records of patients with undescended testis plus hypospadias and/or chordee, and those with ambiguous genitalia who presented between 1986 and 1999. Patients without karyotype determination, and those with iatrogenic cryptorchidism, retractile testes, congenital adrenal hyperplasia or female-appearing external genitalia were excluded from study. Meatus and testis locations at surgery, and associated Müllerian structures and medical conditions were documented. Fisher's exact test was done to determine statistical significance.Of the 113 patients whose records matched study inclusion criteria only 48 had complete anatomical, karyotypic, pathological and radiographic information available. Eight patients (16.7%) had chromosomal abnormalities, including 2 (4.2%) with karyotypic intersex disorder and 6 (12.5%) with autosomal chromosomal abnormalities. There were persistent Müllerian structures in 2 patients (4.2%) with a normal 46 XY karyotype. As described by a staff pediatric urologist, 20 patients (41.7%) had ambiguous genitalia and 8 of the 48 (16.7%) had nonpalpable cryptorchidism. Ambiguous genitalia were associated with chromosomal abnormalities, in 4 of the 20 cases, including 2 karyotypic intersex cases. Only 3 patients with ambiguous genitalia had nonpalpable gonads and 1 with karyotypic intersex disorder had a nonpalpable gonad that involved the testicular elements only. The incidence of autosomal chromosomal abnormalities was not significant (2-tailed Fisher's exact test p==0.05) and the incidence of karyotypic (autosomal or sex) abnormalities was not significant compared with hypospadias (p = 0.3), genital ambiguity (p = 0.7) or cryptorchidism (p = 0.69), including nonpalpable testis (p = 1). When patients had karyotypic abnormalities, they were more likely to have proximal hypospadias (57.2%), palpable cryptorchidism (62.5%) and ambiguous genitalia (50%).Most patients who present for the evaluation of hypospadias, chordee and undescended testis have a normal karyotype. Routine karyotype investigation of all patients with hypospadias, chordee and cryptorchidism does not seem warranted. If karyotypic intersex abnormalities are identified, those patients are more likely to have ambiguous genitalia, especially those with perineal hypospadias and cryptorchidism.

We evaluated the diagnostic accuracy of preoperative localization of impalpable undescended testis using ultrasound and gadolinium (Gd) enhanced magnetic resonance angiography (MRA).Ultrasound and Gd-MRA were performed prospectively in 21 boys (23 impalpable testes) with cryptorchidism before laparoscopy and surgical exploration. Gd-MRA was done using a 1.5 Tesla magnetic resonance scanner with a turbo field echo technique after bolus intravenous injection of 0.4 mmol./kg. body weight of Gd diethylenetriaminepentaacetic acid. A total of 10 dynamic scans were acquired during 15 minutes after Gd injection to cover the early arterial and delayed venous phases. All patients subsequently underwent diagnostic laparoscopy and definitive surgery.Ultrasound correctly localized 9 of 10 intracanalicular testes but failed to reveal any intra-abdominal or vanishing testes. In contrast, Gd-MRA correctly localized 4 intra-abdominal, all 10 intracanalicular and 8 canalicular vanishing testes. In 1 patient with an intra-abdominal vanishing testis ultrasound and Gd-MRA failed to make the diagnosis. When correlated with the findings of subsequent laparoscopy and surgical exploration, Gd-MRA had a diagnostic sensitivity of 96% and a specificity of 100% for localizing impalpable undescended testes. Based on Gd-MRA and ultrasound findings laparoscopy could have been avoided in 18 of 23 cases (78%). No adverse effect was associated with Gd use in this study.Gd-MRA accurately diagnoses vanishing testes and reliably differentiates intraabdominal from intracanalicular impalpable testes, allowing definite preoperative planning of the surgical approach and avoiding unnecessary laparoscopy. A new management algorithm for impalpable testis in patients with cryptorchidism is proposed based on ultrasound and Gd-MRA findings.

This review was performed to assess the effect of protecting the collateral circulation between spermatic and vasal vessels by leaving a strip of peritoneum attached to the lower spermatic cord in patients in whom the spermatic vessels needed to be divided to bring the testis into good scrotal position.Between 1983 and 1994, 22 boys were encountered in whom 1 testis was always normal in size and position, and the other was intra-abdominal and would not be in normal scrotal position after complete cord straightening. A strip of peritoneum had been left attached to the spermatic cord before full mobilization. After high division of the spermatic vessels the testes were brought in the mid scrotum during the same operation.All testes remained in scrotal position except 1 which retracted and was subsequently removed. None became atrophic.Division of the spermatic vessels, the Fowler-Stephens maneuver, can safely be performed during an initial operation as long as its possible need is anticipated, and the collateral circulation between the vasal vessels and spermatics is not disrupted. Secondary orchiopexy for inadequate cord length is now rarely required. This type of open orchiopexy for high impalpable testis is safe, is easy to learn, has no increased morbidity and is generally less expensive than a laparoscopic approach.

PURPOSE: We verified the prevalence of serum antisperm antibodies at diagnosis in a large group of cryptorchid boys, and determined whether it may be influenced by orchiopexy. MATERIALS AND METHODS: We prospectively evaluated serum antisperm antibodies in 186 and 23 boys 0.67 to 14.25 years old with unilateral and bilateral cryptorchidism, respectively, before, and 3, 12 and 24 months after surgery. At diagnosis Tanner stage was 1 and 2 or 3 in 188 and 21 cases, respectively. During the 2-year followup 23 boys entered puberty. A total of 111 normal prepubertal (Tanner stage 1) and 54 pubertal (Tanner stage 2 or 3) boys served as controls. Antisperm antibodies were detected using the tray agglutination and indirect immunobead tests. RESULTS: At diagnosis 29 cryptorchid boys (13.8%) were antisperm antibody positive, including 21 of the 188 prepubertal (11.1%) and 8 of the 21 pubertal (38%) boys (significantly different, chi-square test p

Gonocytes differentiate into spermatogonial stem cells, which make it possible to maintain spermatogenesis continuously throughout life. We previously reported attenuated spermatogonial stem cell activity in cryptorchid testes, which resulted in altered spermatogenesis and affected fertility. However, few groups have examined the differentiation process from gonocytes to spermatogonial stem cells. To clarify the underlying mechanisms comprehensively we performed microarray analysis to assess differential expression of transcripts between normal and undescended testes in juvenile rats.Using microarray analysis we compared whole mRNA expression of normal and cryptorchid testes in a rat model. We subsequently validated differential expression of candidate genes by real-time reverse transcriptase-polymerase chain reaction and performed immunohistochemistry. We also investigated the methylation status of histone H3K4 in cryptorchid testes and the GC-1 spermatogonial cell line.We detected 24 up-regulated and 39 down-regulated genes. Of these genes Kdm5a expression was significantly higher in undescended testes. Immunohistochemistry showed that Kdm5a was localized in the nuclei of gonocytes, spermatogonia and spermatocytes. H3K4me2/me3 expression levels were decreased in undescended testes at 9 days postpartum. Furthermore, Kdm5a over expression in GC-1 cells led to increased expression of Esr2, Neurog3, Pou5f1, Ret and Thy1.Recent investigations revealed that not only genetic but also epigenetic regulation has a role in spermatogenesis. Kdm5a is likely involved in the transformation of gonocytes into spermatogonial stem cells by transcriptional regulation of specific genes via H3K4 histone modification. To our knowledge this is the first report of epigenetic analysis of germ cell differentiation during early spermatogenesis.

Undescended testis is the most common defect in male newborns. This condition is associated with increased risks of infertility and testicular malignancy due to abnormal germ cell development in the testes. Early surgery may limit such risks. We analyzed germ cell development vs age at orchiopexy using a germ cell marker and a Sertoli cell marker on testicular biopsies.A total of 22 testicular biopsies at orchiopexy in 20 patients 5 to 24.5 months old were fixed and embedded in paraffin. Sections were processed and labeled with AMH antibody for Sertoli cells and MVH antibody for germ cells for immunofluorescent histochemical analysis. Confocal images were counted using ImageJ (National Institutes of Health, Bethesda, Maryland) for germ cells and testicular tubules. The data were analyzed using linear regression.Sertoli cells were clearly distinguished from MVH positive and negative germ cells located centrally or on basement membranes of tubules. Percentage of tubules with MVH negative germ cells significantly decreased with increasing age at orchiopexy (β = -0.03, p = 0.03). Total tubular numbers and "empty" tubules without germ cells significantly increased with age at orchiopexy (β = 1.15, p = 0.02 and β = 0.44, p = 0.04, respectively).AMH antibody distinguished Sertoli cells from germ cells, and MVH antibody distinguished 2 types of germ cells at different developmental stages. Biopsy at orchiopexy in older patients showed significant germ cell depletion. These results lend support to early surgery to optimize germ cell number.

There are established variations in testicular cancer incidence between ethnic groups within countries. It is currently unclear whether the occurrence of cryptorchidism-a known risk factor for testicular cancer-follows similar patterns. In New Zealand Māori have unusually high rates of testicular cancer compared to individuals of European ancestry. We hypothesized that ethnic trends in the incidence of cryptorchidism would reflect those for testicular cancer in this setting.We followed 318,441 eligible male neonates born in New Zealand between 2000 and 2010 for the incidence of orchiopexy confirmed cryptorchidism and the incidence of known risk factors for cryptorchidism (low birth weight, short gestation, small size for gestational age) using routine maternity, hospitalization and mortality records. Logistic regression was used to calculate odds ratios for the presence of known risk factors for cryptorchidism by ethnic group. Poisson regression was used to calculate relative risk of cryptorchidism by ethnicity, adjusted for risk factors.Ethnic patterns of cryptorchidism incidence in New Zealand closely mirrored those previously observed for testicular cancer. Māori had higher rates of cryptorchidism than all other ethnic groups (adjusted RR 1.2 [95% CI 1.11-1.3]), with Pacific (0.89 [0.8-0.99]) and Asian groups (0.68 [0.59-0.79]) having the lowest rates (European/other, referent).Since the principal risk factors for cryptorchidism are present in utero, the results of the current study strengthen the likelihood that the ethnic patterning of testicular cancer is at least partly due to prenatal risk factors.

We determined relative semen quality in youths diagnosed with cryptorchidism or varicocele as a surrogate for ultimate paternity potential. We hypothesized that youths with varicocele would be at lower risk for subfertility based on semen analysis than their counterparts with surgically corrected cryptorchidism.We retrospectively reviewed the records of patients with a history of cryptorchidism or varicocele. Patients were placed in 1 of 3 groups based on diagnosis, including group 1-untreated varicocele, group 2-treated bilateral cryptorchidism and group 3-treated unilateral cryptorchidism. Age and semen parameters (density, volume, count, motility and total motile count) were compared for each group.A total of 193 subjects were studied. Median age was 18.3 (IQR 18.1-19.3), 18.6 (IQR 18.3-21.0) and 18.5 years (IQR 18.2-19.6) in the 76 group 1, 21 group 2 and 96 group 3 patients, respectively. Total motile count in groups 1, 2 and 3 was 14.6 (IQR 4.7-29.3), 4.0 (IQR 0-38.0) and 34.1 million sperm (IQR 7.6-90.8), respectively. No significant difference existed between the groups in age, volume (p = 0.106) or motility (p = 0.197). However, density (p = 0.0001), count (p = 0.0001) and total motile count (p = 0.0002) achieved significance. For each of these parameters a significant difference was noted for group 1 vs 3 and group 2 vs 3 but not for group 1 vs 2.The semen quality of youths with varicocele more closely resembles that of youths with bilateral cryptorchidism than those with unilateral cryptorchidism. This is concerning and should challenge current treatment paradigms for adolescents with varicocele.

We studied long-term outcomes of orchiopexy at diagnosis of acquired undescended testes using ultrasound to determine testicular volume.Patients who had undergone orchiopexy for acquired undescended testis at diagnosis were recruited to assess testicular volume. Testis volume was measured by ultrasound and compared with recently developed normative values for testicular size. For young adults (older than 18 years) volumes were grouped and compared to normative values reported in the literature. In all unilateral cases testicular volume was compared with its counterpart.A total of 155 patients 5.1 to 26.6 years old (181 acquired undescended testes) were included in the study. Mean ± SD followup was 6.6 ± 3.8 years (range 1.4 to 15.5). For all patients 18 years old or younger (125 patients, 143 testes) operated testis volume was 0.1 to 12.7 ml (mean ± SD 2.5 ± 2.9), which was significantly smaller than the normative values (50th percentile) for the same age (p0.001). Mean ± SD testis volume in young adults (38 testes) was 8.1 ± 3.7 ml, compared to a mean volume of 13.4 ml reported in the literature (p0.001). In unilateral cases the mean volume of the testes fixed by orchiopexy differed significantly from their counterparts (3.4 ± 3.3 ml vs 4.6 ± 4.6 ml, p0.001).The long-term volumes at diagnosis of acquired undescended testes after orchiopexy were significantly less than the normative values at all ages. In unilateral cases the volumes were also significantly less compared to the contralateral testes.

Recent reports in the literature indicate that laparoscopy tends to be seen as the most appropriate approach to the nonpalpable testis for diagnosis and therapy. The aim of our study was to evaluate the real benefits of laparoscopy in terms of diagnostic accuracy, safety, costs and validity of the chosen treatment.We compared anatomical findings and results of the treatment of impalpable testes in 2 pediatric surgical groups, including 47 children treated laparoscopically during a 2 1/2-year period and 296 treated with open surgery (classic orchiopexy) in a 6 1/2-year period.There was no significant difference in the diagnosis of abdominal testes (51 versus 50%), whereas a difference was noted in inguinal (4 versus 15%) and absent testes (45 versus 35%). Differences in treatment were more striking. In the laparoscopic group standard orchiopexy was performed in 62.5% of cases versus 83% in the open group. Conversely the rate of Fowler-Stephens repairs increased from 5.5% of open surgery cases to 37.5% of laparoscopic cases. There have been no serious complications in the laparoscopic procedures. To date 6 of the 9 patients who underwent a staged Fowler-Stephens procedure have undergone complete repair (open second stage). A review of the literature revealed a similar but lower tendency to over perform the Fowler-Stephens operation in laparoscopic cases (34%) versus open surgery (8%). Also, in previous series there was a 29% orchiectomy rate during laparoscopy compared to only 5% in classic open surgery. In Italy under current public health programs overall costs of the laparoscopic approach to the nonpalpable testis become noncompetitive when the procedure is extended from only diagnostic to interventional use due to the need for additional trocars and other special instruments. In contrast, private health insurers provide an additional 30% for laparoscopic cases over the cost of open orchiopexy.Laparoscopy is definitively accurate in establishing the differential diagnosis of impalpable testis. The number of Fowler-Stephens repairs in the laparoscopic group seems inordinately high, probably due to a lack of definite standards in the proper assessment of the length of the internal spermatic vessel pedicle and the potential scrotal displacement of the testis. This reason may explain the higher number of orchiectomies reported in the literature.

Purpose: We determined whether testis viability after a Fowler-Stephens orchiopexy depends on ligating the spermatic vessels high and far proximal to the undescended testis.Materials and Methods: Based on studies of testicular vascular anatomy we developed a technique of low spermatic vessel ligation and performed it on 39 high undescended testes in 33 patients.Results: Testis viability was 97 percent at 1 month and 93 percent (25 of 27) at 1 year.Conclusions: Ligation of the spermatic vessels does not need to be performed high to ensure testis viability. Testicular vascular anatomy supports low spermatic vessel ligation and by decreasing tension on the testis low spermatic vessel ligation may enhance viability. A 2-stage laparoscopic approach to the high undescended testis is difficult to justify on the basis of cost or outcome analysis.

Purpose: We reviewed the experience, early followup and technique of laparoscopic treatment of the nonpalpable undescended testis at our institution.Materials and Methods: Charts of patients who underwent laparoscopic treatment of an intra-abdominal testis from September 1992 to October 1994 were reviewed.Results: A total of 13 laparoscopic orchiopexies was performed on 11 children with nonpalpable undescended testes. In 10 cases sufficient length was gained on the spermatic vessels using laparoscopic dissection to perform tension-free orchiopexy without the need for division of the spermatic vessels.Conclusions: When localization of an intra-abdominal testis is confirmed, orchiopexy can be performed safely with minimal morbidity using a laparoscopic approach. Length of hospital stay and postoperative morbidity may be improved in comparison to traditional techniques.

In recent series of boys with cryptorchidism gonadotropin levels have been higher and serum inhibin B levels have been lower than normal. To some extent the serum values of inhibin B reflect the state of germinative epithelium in cryptorchid testes. We evaluated whether blood samples of gonadotropins and inhibin B as well as histopathology could be used to classify undescended testes.A total of 69 boys (median age 2 years) who underwent surgery for bilateral cryptorchidism had blood samples taken preoperatively and 3 months to 2.1 years postoperatively. Testicular biopsies were performed bilaterally at orchiopexy. The average germ cell number per tubular transverse tubule was measured.Group 1 included 17 patients with increased follicle-stimulating hormone levels. Serum follicle-stimulating hormone and luteinizing hormone decreased significantly after surgery. In 77% of patients (13 of 17) follicle-stimulating hormone levels were normalized. Of these boys 35% (6 of 17) had a low postoperative serum inhibin B. Group 2 consisted of 27 patients with a decreased germ cell number and/or low preoperative inhibin B, but not increased serum follicle-stimulating hormone or luteinizing hormone. There were no significant postoperative changes in follicle-stimulating hormone and luteinizing hormone. Of these boys 22% (6 of 27) had a low serum inhibin B postoperatively. In group 3 there were 25 patients with a normal germ cell number, normal preoperative serum inhibin B and normal gonadotropins. There were no significant changes in luteinizing hormone and follicle-stimulating hormone postoperatively. Only 1 boy in this group had a low postoperative serum inhibin B.Patients with increased gonadotropin levels may have testicular dysgenesis and some may benefit from early surgery. Patients with normal gonadotropin levels and a decreased germ cell number have transient hypothalamus-pituitary-gonadal hypofunction and a poor fertility prognosis. These patients may benefit from gonadotropin treatment after orchiopexy. Patients with normal gonadotropins, inhibin B and germ cell number have a good fertility prognosis after surgery.

We describe the outcomes of undescended testes and sex development disorders in adolescence and young adulthood. We reviewed the requirements for the long-term care of children born with these and other major congenital anomalies of the genitourinary system.The current English language literature was retrieved with a PubMed® search for articles on these subjects. Only articles covering outcomes at ages past puberty were included in analysis. The material was supplemented from the database of the clinic for adults with sex development disorders at University College London Hospitals.An undescended testis has impaired spermatogenesis. In men in whom a unilateral undescended testis was corrected before puberty the incidence of paternity is normal at around 90% of those who attempt it. The equivalent rate for those with bilateral undescended testes is about 65%. If surgery for bilateral undescended testes is delayed until after puberty, fertility is unlikely. The risk of testicular neoplasms is overestimated and the relative risk is between 2.5 and 8. Children born with a sex development disorder receive multidisciplinary treatment throughout childhood and require the same care as adults. Males who are under virilized likely have a micropenis (greater than 2 SD below the mean stretched length) but they may have normal sexual function. Fertility depends on the underlying condition. Virilized females, who most commonly have congenital adrenal hyperplasia, currently present to adult clinics with an inadequate vagina after infantile surgery. Reconstruction is required to allow intercourse.The care of adults born with abnormalities of the genitalia is complex. Early management may define upbringing in childhood but requirements for sexuality and fertility in adult life are different. Multidisciplinary care is essential and a case can be made to establish a subspecialty of urology to coordinate it.

To elucidate the mechanism of infertility caused by cryptorchidism we focused on early stage spermatogenesis and spermatogonial stem cell activity in undifferentiated spermatogonia in cryptorchid testes.Histological findings and expression patterns of the stem cell marker undifferentiated embryonic cell transcription factor 1 were examined in a unilateral cryptorchid rat model. We removed unilateral descended testis and contralateral descended testis from cryptorchid and normal rats (control), respectively, 18 days postcoitum to 144 days postpartum.In descended testes gonocyte differentiation into early A spermatogonia occurred at 9 days postpartum. However, this transformation was altered in undescended testes. Furthermore, the undifferentiated embryonic cell transcription factor 1 negative early A spermatogonia-to-positive early A spermatogonia ratio was significantly higher in the undescended testis group (mean ± SD 0.69 ± 0.04) than in the control (0.46 ± 0.10, p = 0.037) and descended testis (0.44 ± 0.05, p = 0.022) groups, indicating decreased early A spermatogonia with spermatogonial stem cell activity in cryptorchid testes.In cryptorchid testes the differentiation from gonocytes into early A spermatogonia and the stem cell activity of early A spermatogonia were altered during the early stage of spermatogenesis, suggesting that the loss of spermatogonial stem cell activity in cryptorchid rats resulted in altered spermatogenesis, thus interfering with fertility.

To the Editor: Commenting on imaging for cryptorchidism by primary care providers (PCPs), Elder emphasizes its use in patients with nonpalpable testes. While this is one scenario that may lead PCPs to order ultrasound, our study and that of Tasian et al revealed that imaging is also commonly ordered in boys older than 1 year with palpable testes, indicating that these providers are unaware that ultrasound cannot distinguish a retractile from an undescended testis. We agree with Elder that education to end these practices requires, among other efforts, reports in the pediatric literature to reach PCPs, which we and Tasian and Copp have recently published. However, we also must comment on the review of nonpalpable testes, as it perpetuates misconceptions that hinder discussions between pediatric urologists regarding best management. While it may be true that overall 50% of nonpalpable testes are viable, data from prospective series indicate that findings are significantly different in boys with unilateral vs bilateral nonpalpable testes. Nearly all boys with bilateral nonpalpable testes have bilateral viable testes, whereas the majority (two thirds) of those with a unilateral nonpalpable testis have ipsilateral testicular loss, usually with a scrotal nubbin. The viable testes in the remaining third are found equally within the abdomen and extra-abdominally, meaning that only 15% of patients have an intra-abdominal viable testis. Compensatory hypertrophy of the contralateral descended testis, defined as length 1.8 cm or greater, positively predicts testicular loss in 90% of unilateral cases. From these data a rational approach can be devised that varies with the clinical scenario. Patients with bilateral nonpalpable testes likely have intra-abdominal testes, and initial laparoscopy is reasonable. A boy with a unilateral nonpalpable testis and compensatory hypertrophy on the other side most likely has a scrotal nubbin, and initial scrotal exploration is most efficient. Patients with unilateral nonpalpable testis and no contralateral hypertrophy most likely have a viable testis that, despite careful examination preoperatively and under anesthesia, has a 50% chance of being outside the abdomen. Here is another scenario in which preoperative ultrasound might be considered, to guide the surgeon toward initial laparoscopy vs an extra-abdominal incision. It is not concern about laparoscopy being a risky procedure that leads me most often to begin surgery for the unilateral nonpalpable testis with a scrotal incision. It is the evidence of what I am most likely to encounter, especially when testicular loss is anticipated.

We used ultrasound to determine the volume of retractile testes in boys and compared these volumes with normative testicular volume values.A total of 171 boys were enrolled in the study, of whom 14 were excluded from analysis. The 157 boys included (age 0.8 to 11.5 years) were recruited from 2 different populations. The first subgroup comprised 92 boys previously excluded from a study aimed at obtaining normative values of ultrasonographically scanned testes. The second group included 65 boys who had been referred to our outpatient clinic for nonscrotal testis and who were diagnosed with retractile testis. Testicular volume was measured by ultrasound in a scrotal position or in an inguinal position. Three separate transverse and longitudinal images of each testis were recorded. Length, width and height were measured, and the volume was calculated with the formula for an ellipsoid, π/6 × length × width × height. The highest value of the 3 testicular volumes was determined and taken as the volume measurement.The volumes measured by ultrasound for the 157 boys with 276 retractile testes ranged from 0.18 to 1.49 ml (mean 0.50). The volumes of the retractile testes were significantly smaller than normative values (p0.001). Furthermore, the testicular volumes of retractile testes measured in an inguinal position were significantly smaller than those measured in a scrotal position (p0.001).The volumes of retractile testes are significantly smaller than recently determined normative values.

Fusion anomalies of the testis and epididymis are associated with cryptorchidism. The bilateral histology of the cryptorchid testis associated with the nonfused epididymis has not been reported previously.We retrospectively reviewed patients who presented with unilateral undescended testes and underwent bilateral testis biopsy at orchiopexy between 1982 and 2008. Testes were stratified into groups based on degree of testis-epididymis nonfusion. Age at surgery, testicular volume, testicular position, total germ cells per tubule and adult dark spermatogonia per tubule were compared among all groups.A total of 2,660 testes were eligible for review, of which 2,425 had normal fusion (group 1), 55 had epididymal head nonfusion (group 2), 119 had epididymal tail nonfusion (group 3) and 61 had complete nonfusion (group 4). With increasing degrees of nonfusion trends toward younger age, smaller testicular volume and higher preoperative position were observed. However, testis-epididymis nonfusion was not a significant predictor of abnormal germ cells per tubule or adult dark spermatogonia per tubule in undescended testes and contralateral descended testes.Fusion anomalies are associated with smaller, higher testes with no significant abnormalities in germ cells per tubule or adult dark spermatogonia per tubule. Testis-epididymis nonfusion is not a reliable predictor of reduced histological findings, and should not be a strong consideration when counseling patients and their families about future fertility, especially in instances of complete nonfusion.

Early treatment for cryptorchidism may be necessary to preserve fertility. International guidelines now recommend that congenital cryptorchidism be treated with orchiopexy before age 1 year. Acquired cryptorchidism should be treated at presentation. To our knowledge the rate of adherence to these guidelines in recent years is unknown. Thus, we present data on age at cryptorchidism diagnosis and orchiopexy in recent Danish birth cohorts.A population of 508,964 Danish boys born alive from January 1, 1995 to December 31, 2009 was identified using the Danish Civil Registration System. Five birth cohorts were defined, including 1995 to 1997, 1998 to 2000, 2001 to 2003, 2004 to 2006 and 2007 to 2009. The boys were followed in the Danish National Patient Registry for a diagnosis of cryptorchidism and for an orchiopexy procedure. Data were analyzed using the Kaplan-Meier estimator and Cox regression models.During followup 10,094 boys were diagnosed with cryptorchidism, of whom 5,473 underwent orchiopexy. Mean age at diagnosis in boys followed at least 6 years was 3.3 years (95% CI 3.3-3.4) in the 1995 to 1997 cohort, 3.1 (95% CI 3.1-3.2) in the 1998 to 2000 cohort and 2.9 (95% CI 2.8-2.9) in the 2001 to 2003 cohort while mean age at orchiopexy was 3.8 (3.7-3.9), 3.6 (3.5-3.7) and 3.3 years (3.2-3.4), respectively.In the more recent birth cohorts of 1995 to 2009 we observed a shift toward younger age at cryptorchidism diagnosis and orchiopexy.

We determined the incidence of acquired undescended testes in boys with hypospadias.We retrospectively reviewed the records of 566 boys with hypospadias who were referred to our outpatient clinic between January 2000 and September 2009. Acquired undescended testes were defined as testes that were documented at the bottom of the scrotum at least once after birth by the pediatric urologist at our institution but were subsequently documented to have moved from a satisfactory scrotal position by the same pediatric urologist or an equally experienced pediatric urologist. However, this definition did not include undescended testes after inguinoscrotal surgery. We excluded boys with gender development disorders with testicular dysgenesis, those who underwent bilateral inguinoscrotal surgery and those without congenital cryptorchidism who were followed less than 3 months.Of the 566 boys with hypospadias 100 met study exclusion criteria. Of the 466 boys included in analysis 29 (6.2%) had congenital cryptorchidism and 15 (3.2%) had acquired undescended testes. Urethroplasty was performed in 413 boys, including 91 with distal, 132 with mid and 181 with proximal hypospadias. The incidence of congenital cryptorchidism and acquired undescended testes in boys with proximal hypospadias was significantly higher than that in boys with other types of hypospadias (p = 0.03 and 0.001, respectively).Boys with proximal hypospadias are at a higher risk for acquired undescended testes than those with other mild types of hypospadias. Thus, testicular location should be monitored regularly until after puberty.

The surgical approach to palpable and nonpalpable testicles has changed with increasing use of a single scrotal incision and laparoscopy, respectively. We identified current trends in the surgical approach to undescended testicles in the practice of a single surgeon at our institution.A total of 580 orchiopexies were performed in 554 patients by a single surgeon between January 2002 and July 2009. Study inclusion criteria were palpable and nonpalpable primary undescended testicles. Patients were stratified into groups based on the date of the initial procedure by year. A retrospective chart review was performed and the surgical approach in each patient was recorded as laparoscopic, transinguinal abdominal, inguinal or scrotal.During the 7-year period the percent of orchiopexies performed through a single scrotal incision increased from approximately 15% to a high of 63%. The overall percent of cases performed through a standard inguinal incision decreased from 65% to 17% and the percent performed through a transinguinal abdominal approach decreased from 15% to 0% in the 2 most recent years tabulated. The use of laparoscopy increased from 3% to 17%.Substantial trends were observed among the 3 groups. The percent of procedures performed through a scrotal incision increased during the 7-year period while the percent of inguinal and transinguinal abdominal procedures decreased concomitantly with no increase in morbidity. Selected use of scrotal approach orchiopexy is safe and effective for palpable undescended testicles.

A number of variables should be assessed during laparoscopic orchiopexy, including vas anatomy. A looping vas deferens enters the inguinal canal and loops back to the abdominal cavity. This anatomical variant is not uncommonly encountered. Some groups considered this condition in their laparoscopic classification of nonpalpable testis. We present our experience with managing the looping vas during laparoscopic orchiopexy.We identified this condition in 18 procedures. In 14 cases it was possible to bring the vas back to the abdominal cavity. In 3 cases the loop could not be brought back laparoscopically and an inguinal incision was used. After the vas was dissected free and dropped into the abdominal cavity pneumoperitoneum was resumed and the procedure was completed laparoscopically. A Web based survey was done to test the value of this method.A total of 17 procedures were completed successfully with preservation of the vas deferens while in 1 the vas was inadvertently cut. A looping vas did not significantly affect operative time. All 18 testes were viable and retained the scrotal position on followup scrotal Doppler ultrasound.Verification of vasal anatomy is a crucial step that should be completed before any dissection. Bringing a looping vas back to the abdominal cavity is usually feasible laparoscopically but in a few cases this may require a small incision to dissect the vasal loop from its inguinal attachments.

We compared the results of low transscrotal mid raphe orchiopexy, high scrotal incision (Bianchi) and conventional inguinal approach in patients with palpable undescended testes.Orchiopexies performed between January 2003 and September 2009 with a minimum 3-month followup were included. Low scrotal incision (group 1) and high scrotal incision (group 2) were compared to the traditional inguinal 2-incision technique (group 3). We retrospectively reviewed operative time, success as defined by mid or lower scrotal position of the testis, and complications at 12 weeks and 1 year postoperatively.A total of 286 orchiopexies were performed in 214 patients with palpable undescended testes. Group 1 included 81 patients with 125 undescended testes. Group 2 consisted of 44 patients with 60 undescended testes. Group 3 included 89 patients with 101 undescended testes. Postoperatively the testes were located in a good position within the scrotum in 99% of patients in group 1, 98% in group 2 and 100% in group 3. Mean±SD operative time for unilateral undescended testes was significantly shorter for low transscrotal compared to inguinal orchiopexy (28±10 vs 37±12 minutes, p0.0001) but equivalent to a high scrotal incision (27±10 minutes, p=0.59). For all 160 children followed for 1 year no long-term atrophy or secondary reascent was observed.Low transscrotal mid raphe orchiopexy appears to be an excellent alternative to high scrotal incision or standard inguinal orchiopexy for low palpable undescended testes, especially bilateral cases.

We determine how the proximal gubernaculum testis is attached to the testis and epididymis in human fetuses, and compare these data with findings in boys who had undergone surgery for cryptorchidism.We analyzed 280 testes and epididymides with the gubernacula of 140 well preserved, fresh human fetuses ranging from 10 to 35 weeks after conception with no detectable congenital malformations and 36 undescended testes of 28 boys 2 to 15 years old (mean age 6.8) who had undergone surgery for cryptorchidism. In both groups the different conformations of the relationship among the proximal gubernaculum, testis and epididymis were classified according to a system used for patients with cryptorchidism. In group A the gubernaculum is attached to the testis and epididymis, in group B the gubernaculum is attached only to the testis with a tail disjunction epididymal anomaly, in group C the gubernaculum is attached only to the testis with total disjunction of the epididymis, in group D the gubernaculum is attached only to the epididymal tail and in group E there are no attachments among gubernaculum, testis and epididymis.Of the 280 fetal testes studied 194 (69.2%) were in the abdomen, 38 (13. 57%) in the inguinal canal and 48 (17.14%) in the scrotum. There were 277 cases (98.9%) in group A and 3 (1.1%) in group B. Of the 36 undescended testes analyzed 2 (5.6%) were abdominal and 34 (94.4%) were inguinal. There were 26 cases (72.2%) in group A, 8 (22.2%) in group B and 2 in group D.In fetuses without congenital malformations or epididymal alterations, such as tail disjunction or elongated epididymis, the proximal portion of the gubernaculum was attached to the testis and epididymis in all cases. In undescended testes there was an increased incidence of paratesticular structure malformations accompanied by gubernacular attachment anomalies compared to the testes in normal fetuses.

In the last century the world has experienced an increase in the use of industrial chemicals as well as possible increases in the prevalence of hypospadias and cryptorchidism. Because hormones regulate the fetal development of many organs, numerous investigations have explored the role of environmental factors in genitourinary growth. We summarize the data regarding endocrine disruptors in human genitourinary development.A PubMed literature search was performed for human studies from 2004 to 2009.Few data exist on environmental influences on the kidneys, ureters or bladder. Studies on the influence of pesticides, vegetarian diets, diethylstilbestrol, oral contraceptives and corticosteroids on hypospadias have yielded varied conclusions. Phthalates appear to increase the odds of hypospadias and anogenital distance. The testicular dysgenesis syndrome postulates that cryptorchidism, hypospadias, poor semen quality and testicular cancer share a common environmental origin. In utero exposure to diethylstilbestrol has been shown to increase the risk of testicular dysgenesis syndrome. However, to our knowledge no other environmental factor has been shown to cause testicular dysgenesis syndrome. Some industrial chemicals as well as the pesticide dichloro-diphenyl-trichloroethane have detrimental effects on semen quality. In cases of documented industrial accidents, chemical exposure has also decreased the male-to-female birth ratio.Data on chemical exposure are largely mixed and inconclusive. Studies of populations with high exposure rates due to industrial accidents or in utero exposure to diethylstilbestrol suggest that endocrine disruptors adversely affect genitourinary development.

Purpose: Irrespective of the surgical technique chosen to treat high undescended testis, preservation of an adequate arterial supply for the testis is crucial for successful orchiopexy with maintenance of normal testicular size and texture. To provide an anatomical background for such a procedure, we performed a systematic study on the number and origin of arteries supplying the fetal testis during its migration from the abdomen to the scrotum. Materials and Methods: We studied bilaterally 64 testes from 32 fresh human fetuses 13 to 33 weeks after conception. The fetuses were injected through the thoracic aorta with a microvascular silicone rubber red resin to fill in the arterial tree, thereby enabling identification and dissection of all arteries supplying the testes. Results: Of the 64 testes 3 arteries (testicular, deferential and cremasteric) were found in 46 (71.9%), 2 (testicular and deferential) in 15 (23.4%) and 4 in 3 (4.7%). Conclusions: The fetal testis is always supplied by Eat least 2 arteries (testicular and deferential arteries) and by 3 or 4 arteries in nearly 80% of the cases.

We determined the relationship between clinical variables and testicular histopathological changes associated with decreased fertility potential in children with cryptorchidism.Testis biopsies of 274 children who underwent orchiopexy and concurrent testicular biopsy between 1991 and 2001 were analyzed for germ and Leydig cell loss, and testicular fibrosis. Multivariable logistic regression was used to determine if age at orchiopexy (analyzed as continuous and ordinal variables), preoperative testis palpability, unilateral vs bilateral disease and/or side of undescended testis was predictive of these pathological outcomes.Age at orchiopexy was associated with germ and Leydig cell depletion. Each month of testis undescent was associated with development of moderate/severe germ cell depletion (OR 1.02 for each month of age, p0.005) and Leydig cell loss (OR 1.01 for each month of age, p0.02). Nonpalpable testes were associated with severe germ cell depletion. Children with palpable testes had lower odds of germ cell depletion than those with nonpalpable testes (OR 0.46, p0.005). This finding corresponds to a significant 2% risk per month of severe germ cell loss and 1% risk per month of Leydig cell depletion for each month a testis remains undescended, and a 50% greater risk of germ cell depletion in nonpalpable relative to palpable cryptorchid testes.Testes that remain undescended are associated with progressive loss of germ and Leydig cells, and nonpalpable testes predict severe germ cell loss.