Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism.

PURPOSE: An attempt to make a rational strategy for treatment of cryptorchidism. MATERIALS AND METHODS: 1,335 cryptorchid boys with biopsy at surgery (1,638 specimens). We studied: frequency of no germ cells in biopsies from 698 patients <12 years at surgery; fertility potential of 140 patients who were now adults, and apperance of testicular neoplasia in all biopsies. RESULTS: Lack of germ cells appeared from 18 months. The frequency increased with increasing age. It appeared in 30% (61/202) bilateral, and 18% (88/496) unilateral cases. In men who had undergone bilateral or unilateral orchiopexy, respectively, there was normal sperm count in 19% (14/75) and 83% (54/65), and infertility was suspected in 56% (42/75) and 8% (5/65) (FE, p < 0.00005, p < 0.00005), respectively. The lowest, the mean, and the highest age-matched spermatogonia count per tubule at orchiopexy was associated with sperm count (Spearman test, p < 0.0001, p < 0.005, p < 0.05). Isolated, this was demonstrated for the 75 formerly bilateral (Spearman, p < 0.0001, p < 0.0001, p < 0.0001), but not the 65 formerly unilateral cases (Spearman, p = 1.0). No germ cells at orchiopexy was associated with suspected infertility. Risk was 78-100% in bilateral (dependent on one or both testes affected), and 33% in unilateral cryptorchidism. There was one invasive germ cell tumor, six cases of carcinoma in situ testis, and one Sertoli cell tumor. Three neoplasms were diagnosed in intra-abdominal testes, four in boys with abnormal external genitalia, and two in boys with known abnormal karyotype. Risk of neoplasia was 5% (7/150) in patients with intra-abdominal testis, abnormal external genitalia or diagnosed abnormal karyotype, versus 0% (0/1,185) in patients without these characteristics (FE, p < 0.00005). CONCLUSION: We recommend surgery for cryptorchidism before 15-18 months of age because: (a) lack of germ cells is very rare before, and (b) lack of germ cells is associated with subsequent risk of infertility. At primary surgery for cryptorchidism, we recommend examination for testicular neoplasia in cases of intra-abdominal testis, abnormal external genitalia or known abnormal karyotype.

Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism.

PURPOSE: In boys with cryptorchidism older than 2 years a testicular biopsy at time of orchiopexy shows lack of germ cells in 10-40% of the cases. The number of spermatogonia per tubule is prognostic for subsequent fertility potential. A biopsy without germ cells is associated with 33-100% risk of infertility. In order to increase the number of germ cells, and thereby the fertility potential, additional hormonal therapy has been attempted before surgery. In a study, small doses of the gonadotropin-releasing hormone analogue buserelin before orchiopexy caused higher values. Others have found that hormonal treatment with human chorionic gonadotropin or gonadotropin releasing hormone analogue may harm the germ cells in cryptorchidism. The aim of the study is to demonstrate that additional hormonal therapy with erythropoietin has a positive effect on the number of germ cells. MATERIALS AND METHODS: Erythropoietin (Eprex) 100 IU/kg were administered subcutaneously weekly for 3 months prior to surgery in two cryptorchid boys, 6 months old and 1 year 9 months old, respectively, with renal function impairment. RESULTS: The number of spermatogonia per tubular cross-section in testicular biopsies was unusually high in both erythropoietin- treated cryptorchid cases compared to the control material of biopsies from the undescended testes of 698 cryptorchid patients and compared to the normal values. CONCLUSION: There are several hypothetic mechanisms that can explain the elevated number of spermatogonia seen in our erythropoietin treated cryptorchid patients. Erythropoietin may have a positive effect on germ cell proliferation in cryptorchidism.

Anti-MIC2 as a tool in examination of testicular biopsies.

MIC2 is a pseudoautosomal gene localized on X and Y chromosomes. The MIC2 gene product is a glycoprotein expressed on the cell membranes of a number of somatic cells, including Sertoli cells of the testis, but not on the cell membranes of germ cells. In cases of cryptorchidism, a testicular biopsy is recommended in order to evaluate future fertility potential. The spermatogonia are identified on histological sections and the number per tubular transverse section is compared with normal values for age. The patient is at 33-100% risk of subsequent infertility when the number of spermatogonia per tubular transverse section is lower than 1% of the lowest normal age-matched value. Besides Sertoli cells the seminiferous tubules in undescended testes contain only a few germ cells, and it may be difficult to pinpoint the germ cells in small biopsies. Especially in nonpalpable testes their number may be heavily reduced. A reliable identification of germ cells may also be difficult in cultures of testicular biopsies from undescended testes. Against this background, we tried the use of an immunohistochemical method with DAKO antibody to the MIC2 gene product (MIC2, 12 E7, code no. M3601) in order to obtain a "negative reaction" of germ cells, contrasting with the stained Sertoli cells. The material comprised: 44 specimens of testicular parenchyma taken at time of surgery for cryptorchidism from 24 cryptorchid boys with nonpalpable testes and 14 testicular biopsies from 13 cryptorchid patients with palpable testes which had been cultured in vitro for 7, 14 or 21 days. In all cases the immunohistochemical method with DAKO antibody to the MIC2 gene product was helpful for identification of Sertoli cells and germ cells, and we therefore recommend the use of anti-MIC2 in all testicular biopsies where it is difficult to pinpoint the germ cells.

Germ cells may survive clipping and division of the spermatic vessels in surgery for intra-abdominal testes.

PURPOSE: Laparoscopy is a well described modality that provides an accurate visual diagnosis upon which further management of intra-abdominal testes may be based. Laparoscopic ligation of spermatic vessels as stage 1 of the procedure is a natural extension of laparoscopy. A staged approach provides adequate viability of the intra-abdominal testis. However, it is uncertain whether the more sensitive germ cells survive this procedure in addition to the Sertoli and interstitial cells of the human testis. Survival of germ cells is a prerequisite of later fertility potential. MATERIALS AND METHODS: We studied 17 nonpalpable testes in 10 patients 1 year and 7 months to 13(1/2) years old. Results of testicular biopsies of 13 intra-abdominal testes taken at stages 1 and 2 of surgery were available for histological comparison. RESULTS: Median number of spermatogonia per tubular cross section of the biopsies taken at stage 2 was slightly lower (0.03) compared to the median number at stage 1 (0.06) of the operation but this difference was not significant (p = 0.2031). CONCLUSIONS: Our study shows that the spermatogonia may survive clipping and division of the spermatic vessels, although the number of spermatogonia per tubular transverse section decreases slightly.

[Renal and urinary tract abnormalities in small children]. / Nyre- og urinvejsabnormiteter hos småbørn.

The purpose of this study was to investigate frequency and pattern of urological abnormalities in children younger than two years of age in the county of Frederiksborg, Denmark, with a catchment area of about 350,000 people, and furthermore to investigate in which way the urological abnormalities were diagnosed. From 1994-1996 a total of 35 children younger than two years of age were found to have urological abnormalities. Fourteen patients had a ultrasonographical prenatally diagnosed urological abnormality, which was confirmed postnatally. Twenty-one children were diagnosed with urological abnormalities after presentry with their first urinary tract infection. The obstructive urological diagnoses: congenital hydronephrosis, congenital megaureter and posterior urethral valves made up to 57% (20/35) of the abnormalities. Nine boys were operated upon; three for unilateral hydronephrosis, two for posterior urethral valves, one for unilateral megaureter and three for phimosis. Two girls were treated with oestrogen for labial fusion. Urological abnormalities which were treated were found among the ultrasonographically diagnosed abnormalities, apart from phimosis and labial fusion. The frequency of urological abnormalities was 0.25% in children younger than two years of age in Frederiksborg county. In conclusion, in 1994-1996 the frequency and pattern of urological abnormalities in Frederiksborg county was in accordance with the figures in the literature. Urological abnormalities requiring treatment were diagnosed in 11 children; 55% (6/11) ultrasonographically and 45% (5/11) by examination of the external genitalia of children younger than two years of age at the time of the first diagnosed urinary tract infection.

[Eosinophilic cystitis in children]. / Eosinofil cystitis hos børn.

Eosinophilic cystitis is an inflammatory disorder of the urinary bladder, characterised by irritative voiding symptoms, negative urine cultures, and eosinophilic infiltration of the bladder wall. Since 1960 only about 20 cases have been described in the English scientific reports, making it a rather rare entity. In children the disease appears to be shortlived and self-limited, requiring no specific treatment. We present a case with a 7.5-year-old boy, who experienced spontaneous remission of all symptoms, following an acute attack of eosinophilic cystitis.

Cryptorchidism as a caudal developmental field defect. A new description of cryptorchidism associated with malformations and dysplasias of the kidneys, the ureters and the spine from T10 to S5.

Cryptorchidism is a feature of abnormalities in the hypothalamo-pituitary-testicular axis, and almost all disorders of sexual differentiation in which a testis is present. We found cryptorchidism to be associated with malformations and dysplasias of the kidneys, the ureters and the spine from T10 to S5. The description of this association is new. The association was seen in 18% of cryptorchid boys younger than 3 years of age in a department of paediatric surgery, in 34% of cryptorchid foetuses who died in the third trimester, in 65% of cryptorchid patients with imperforate anus, and in all individuals with tritonmelia, the male variant of sirenomelia. Sirenomelia/tritonmelia is an extreme degree of abnormal differentiation of the caudal developmental field, also called caudal dysplasia, the caudal regression syndrome and the caudal regression malformation sequence. Caudal developmental field defects were also the predominant abnormalities in the other groups of patients. Thus, cryptorchidism may be a feature of abnormal differentiation of the caudal developmental field. Position and histology of the undescended testes of the patients included in the association were similar to in cryptorchidism in general. In the literature the association was reported in 5-10% of boys considered to suffer from cryptorchidism only. Furthermore, our observations are concordant with recent theories about cryptorchidism. Consequently, we propose that cryptorchidism in general may be a caudal developmental field defect. Study of cryptorchid patients exhibiting malformations or dysplasias of the kidneys, the ureters or the spine from T10 to S5 is essential in order to isolate new genetic disorders and to spot environmental factors causing cryptorchidism.

Is infertility after surgery for cryptorchidism congenital or acquired?

We evaluated whether deletions of the DAZ (deleted in azoospermia) gene, abnormal karyotypes or hypogonadotropic hypogonadism (HH) were demonstrable in infertile men who had undergone surgery in childhood for cryptorchidism with a simultaneous testicular biopsy that demonstrated no or almost no germ cells. In six men with infertility after surgery for cryptorchidism, the adult karyotype and analyses for the DAZ gene, serum follicle-stimulating hormone, luteinizing hormone, and testosterone were performed from a peripheral blood sample. Testicular volume was also measured. All patients exhibited a 46,XY karyotype. There were no deletions of the DAZ-gene, no HH and no testicular atrophy. The infertility was thus not proved to be congenital, and consequently, surgical treatment is indicated before the germ cells disappear from undescended testes. This appears to be before 15 months of age.

Prenatal hydronephrosis caused by aberrant renal vessels: a follow-up challenge. Reports of two cases.

With routine use of obstetric ultrasonography, fetal low-grade hydronephrosis is commonly detected, but may resolve spontaneously after birth. Two cases are presented to illustrate that in some cases such findings can express intermittent hydronephrosis caused by aberrant renal vessels. Renal deterioration later in childhood may be a consequence.

[Vesico-amniotic shunt-therapy in fetal obstructive uropathy]. / Vesikoamniotisk shunt-terapi ved føtal obstruktiv uropati.

Due to the widespread use of obstetric ultrasound an increasing number of congenital malformations are diagnosed prenatally. Some of these can be treated in utero. A 17 week-old fetus with a posterior urethral valve was diagnosed due to a dilated bladder, bilateral hydronephrosis and oligohydramnios. An ultrasonically guided vesicoamniotic shunt was successfully placed in utero at 24 weeks of gestation in order to prevent development of dysplastic kidneys and hypoplastic lungs. Transurethral valve resection was performed five months postnatally. The one year-old infant is now well and has one normally functioning kidney.

Fertility potential after unilateral orchiopexy: an age independent risk of subsequent infertility when biopsies at surgery lack germ cells.

PURPOSE: We evaluated whether adult fertility potential was better when unilateral orchiopexy was done at ages 2 to 6 years or later, and we identified those at risk for infertility. MATERIALS AND METHODS: Unilateral orchiopexy was performed simultaneously with testicular biopsy in 11 patients 2.8 to 6.8 years old and in 54, 10.0 to 11.9 years old. In adulthood measurement of testicular volume, serum follicle-stimulating hormone, luteinizing hormone and testosterone was done, as well as analysis of semen specimens. RESULTS: At orchiopexy the 2 groups were statistically similar, and statistically similar fertility potentials were found in adulthood. Five of the 65 patients (7.7%, 95% confidence limits 2.5 to 17%) may experience infertility, representing 33% of both groups with less than 1% of the age matched number of spermatogonia per tubular transverse section (approximately no germ cells) in the biopsy specimen at orchiopexy. CONCLUSIONS: Between ages 2 and 12 years the timing of unilateral orchiopexy may vary without an effect on subsequent fertility potential. When biopsy at surgery lacks germ cells, there is an approximately 33% age independent risk of subsequent infertility. Otherwise patients may be fertile after unilateral orchiopexy between ages 2 and 12 years.

[Cryptorchidism in boys with anal atresia]. / Kryptorkisme hos drenge med anal atresi.

In a retrospective study of the case reports of 136 boys who were operated on for an imperforate anus and who survived at least 18 months, cryptorchidism was the most common associated anomaly, involving 26 cases (19%). The higher the level of the anorectal malformations, the higher was the incidence of cryptorchidism. The incidence of renal and ureteric malformations and dysplasias showed a parallel tendency. The incidence of vertebral malformations and dysplasias in the T10-S5 area was low among patients with a covered anus or a perineal fistula. Cryptorchidism was found to be associated with urological and with T10-S5 vertebral malformations and dysplasias. Recognition of this association is probably new. The histopathological findings of testicular biopsy specimens and the location of the undescended testes in patients with an imperforate anus showed the same pattern as seen in undescended testes from patients with cryptorchidism only. These findings, together with the existing literature on the subject, indicate that further studies on the association of cryptorchidism, urological, and T10-S5 vertebral malformations and dysplasias may be important for a better understanding of cryptorchidism in general.

[Laparoscopy in 100 consecutive patients with 128 impalpable testes]. / Laparoskopi af 100 konsekutive patienter med 128 ikkepalpable testes.

A cohort of 100 patients underwent laparoscopy for 128 impalpable testes. They ranged in age from 2.7 to 19.3 years (median 10.8 years). There were no complications associated with laparoscopy. In 50% of the cases either blindending cord structures above the internal inguinal ring or intra-abdominal testes were identified; in the remainder, cord structures could be seen passing through the ring, indicating an intracanalicular testis. The impalpable testis was absent in 77% of patients with a contralateral scrotal testis. A seminoma was found in one 18.6-year-old patient with bilateral cryptorchidism. No intratubular germ cell neoplasia (carcinoma in situ) was proved. Germ cell hypoplasia or aplasia was demonstrated in 95% of cases with testicular parenchyma. We recommend laparoscopy as a safe procedure which leads to a diagnosis in patients with impalpable testes; the advent of laparoscopic procedure makes definitive treatment possible in about 50% of such cases.

Fertility potential after unilateral orchiopexy: simultaneous testicular biopsy and orchiopexy in a cohort of 87 patients.

PURPOSE: We investigated the prognostic value of the number of spermatogonia per tubular cross section in a testicular biopsy specimen obtained at orchiopexy for unilateral cryptorchidism. MATERIALS AND METHODS: A total of 87 consecutive 10 to 12-year-old cryptorchid boys underwent testicular biopsy simultaneously with unilateral orchiopexy. In adulthood 56 of the 87 patients agreed to measurement of serum follicle-stimulating hormone, luteinizing hormone, testosterone and testicular volume, and 54 provided specimens for semen analysis. RESULTS: The number of spermatogonia per tubular cross section correlated to the volume of the operated testis and total testicular volume in adulthood. Serum follicle-stimulating hormone negatively correlated to these volumes, sperm concentration and total sperm count. Contralateral testicular volume correlated to sperm concentration, total sperm count, and percent of living and mobile sperm. When biopsy revealed Sertoli cells only or 1 spermatogonium per 100 tubular cross sections, the age matched number of spermatogonia per tubular cross section was 1% or less. Of these patients 33% later presented with 5 million spermatozoa per ml. or less, no normal motility and generally lower sperm concentrations that those with more than 1 spermatogonium per 100 tubular cross sections (greater than 1%) in the biopsy specimen. When the value was greater than 1%, later sperm quality was not significantly reduced in comparison to that of the general population. CONCLUSIONS: The age matched number of spermatogonia per tubular cross section is significant in regard to fertility potential, and a value of 1% or less (approximately Sertoli cells only) may predict low fertility potential. To our knowledge Sertoli cells only have not been observed before 15 months of life, which makes it logical to treat cryptorchidism before this age even in unilateral cases.

The pathogenesis of cryptorchidism and splenogonadal fusion: a new hypothesis.

OBJECTIVE: To obtain new information about the pathogenesis of cryptorchidism. MATERIALS AND METHODS: Published reports of 111 males with splenogonadal fusion were examined and the presence and type of cryptorchidism and the degree of continuity between the spleen and gonads determined. RESULTS: Of the 111 cases, 31% had cryptorchidism and of these 59% were bilaterally cryptorchid; 26% and 65% had right and left intra-abdominal testes, respectively. Of those with continuous splenogonadal fusion, 44% had cryptorchidism. Solely cryptorchid cases with splenogonadal fusion had reported bilateral absence of both legs, imperforate anus, spina bifida, diaphragmatic hernia and hypospadias. CONCLUSION: An hypothesis is proposed that the abnormal development of the diaphragmatic ligaments of the testes may lead to lack of their involution, with consequent cryptorchidism. In the case of splenogonadal fusion, the abnormal ligaments are colonized by splenic cells, possibly because of an abnormal proximity to the splenic anlage, with the resulting abnormal ligament persisting as the splenic cord and thus resulting in cryptorchidism. The basic abnormality may be in the connections of the diaphragmatic ligaments, caused by abnormal midline development in the third to fourth week of gestation.

Urodynamics in boys after prenatally diagnosed vesicoureteric reflux.

Over the years, several theories have been presented regarding the pathogenesis of vesicoureteral reflux (VUR) in children without neurological disease or posterior urethral valves. Primary VUR is one of many fetal uropathies detectable by prenatal sonography. Thirteen boys with a prenatal diagnosis of hydronephrosis and postnatally demonstrated VUR had a urodynamic evaluation carried out at the age of 1 to 26 weeks. The renal function was evaluated by renography and estimation of glomerular filtration rate. Maximum detrusor pressure at voiding was significantly higher in the group of patients with VUR and impaired renal function compared to: (1) reflux patients with bilateral normal renal function; and (2) "normal" controls. Patients with normal bilateral renal and bladder function had a low risk of urinary tract infection during the period of follow-up (1 to 6 years). Early urodynamic studies in infants with VUR are important in order to clarify the pathogenesis of reflux and plan treatment strategy.

Quantitative histology of germ cells in the undescended testes of human fetuses, neonates and infants.

PURPOSE: We investigated the number of germ cells per tubular cross section and testicular weight in cryptorchid fetuses, neonates and infants, and characterized additional abnormalities. MATERIALS AND METHODS: Our series comprised 35 fetuses and 58 boys with cryptorchidism, and 22 normal fetuses and 25 normal boys. Age ranged from 28 weeks of gestation to 3 years. RESULTS: Cryptorchid fetuses had reduced germ cells per tubular cross section values and lower testicular weights. Values were reduced in cryptorchid boys without a symptomatic inguinal hernia. If a hernia was present, values were normal in the first year of life but decreased at age 1 to 3 years. Malformations or dysplasia of the kidneys, ureter or T10 to S5 vertebrae were present in 34% of the cryptorchid fetuses and 18% of the cryptorchid boys without a symptomatic inguinal hernia. CONCLUSIONS: Our study suggests a reduced number of germ cells in undescended testes from week 28 of gestation and germ cell hypoplasia as a consequence of continued postnatal undescended testicular position. Cryptorchidism may result from abnormal development of the caudal developmental field.

Cryptorchidism in boys with imperforate anus.

In a retrospective study of the case reports of 136 boys who were operated on for an imperforate anus and who survived at least 18 months, cryptorchidism was the most common associated anomaly, involving 26 cases (19%). The higher the level of the anorectal malformations, the higher was the incidence of cryptorchidism. The incidence of renal and ureteric malformations and dysplasias showed a parallel tendency. The incidence of vertebral malformations and dysplasias in the T10-S5 area was low among patients with a covered anus or a perineal fistula. Cryptorchidism was found associated with urological and with T10-S5 vertebral malformations and dysplasias. Recognition of this association is probably new. The histopathological findings of testicular biopsy specimens and the location of the undescended testes in patients with an imperforate anus showed the same pattern as seen in undescended testes from patients with cryptorchidism only. These findings, together with the existing literature on the subject, indicate that further studies on the association of cryptorchidism, urological, and T10-S5 vertebral malformations and dysplasias may be very helpful toward a better understanding of cryptorchidism in general.

Laparoscopy in 100 consecutive patients with 128 impalpable testes.

OBJECTIVE: To investigate the value of laparoscopy in boys with impalpable testes, to carry out a histological examination of testicular biopsies or orchidectomy specimens, and to present a clinical description of boys with impalpable testes. PATIENTS AND METHODS: One hundred consecutive patients underwent laparoscopy for 128 impalpable testes. They ranged in age from 2.7 to 19.3 years (median 10.8). Histological examination was performed on 39 testicular biopsies, nine primarily orchidectomized testes and 13 tissue samples from the end of blind-ending vessels and vasa deferentia. Any additional diagnoses to that of impalpable testes were recorded. RESULTS: There were no complications associated with laparoscopy and the procedure clarified the situation in all patients. In 50% of patients either blind-ending cord structures above the internal inguinal ring or intra-abdominal testes were identified; in the remainder, cord structures could be seen passing through the ring, indicating an intracanalicular testis. The impalpable testis was absent in 77% of patients with a contralateral scrotal testis. A seminoma was found in one 18.6-year-old patient with bilateral cryptorchidism. No intratubular germ cell neoplasia (carcinoma in situ) was found. Germ cell hypoplasia or aplasia was demonstrated in 95% of patients with testicular parenchyma. Additional diagnoses were made in 49% of patients with bilaterally undescended testes (one or both of which were impalpable). CONCLUSION: We recommend laparoscopy as a safe procedure which leads to a diagnosis in patients with impalpable testes; the advent of laparoscopic procedures makes definitive treatment possible in about 50% of such patients. Open procedures will be indicated only to ascertain the quality and treatment of intracanalicular testes.

[Biliary tract atresia. Hepatoportoenteric anastomosis and/or liver transplantation]. / Galdevejsatresi. Hepatoportoenteroanastomose og/eller levertransplantation.

Long-term survival of biliary atresia patients after Kasai hepatoportoenterostomy is being increasingly reported. Favorable prognostic factors are: 1) Young age at operation (max. 60 days). 2) Few incidents of postoperative cholangitis. Jaundice-free long-term survival is achieved in one-fourth to one-third of patients undergoing Kasai hepatoportoenterostomy. Without treatment the average life span is 19 months. Twenty infants with biliary atresia were treated with the Kasai operation between 1976 and 1992. Nine children are alive 11 months to 16 years postoperatively, two after a liver replacement, one at ten months and one at two and a half years old. A tenth child had a well functioning anastomosis but died of heart failure. Eight children with a well functioning anastomosis were all younger than 60 days at the operation. Only one child older than 60 days survived without a liver transplantation. Our results confirm that early diagnosis and treatment of biliary atresia, before 60 days of age, is necessary.