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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.

Animals↗

Clinical diagnosis of cryptorchidism. John Radcliffe Hospital Cryptorchidism Study Group.

We examined 3534 boys for cryptorchidism at birth, and, if present, again at 3 months of age. We compared Scorer's standard criterion for cryptorchidism, based on measurement of the testis from the public tubercle, with the simpler criterion of whether the testis was in the normal position, well down in the scrotum. At birth 210 (5.9%) boys were cryptorchid by measurement and 220 (6.2%) by position. By 3 months of age the cryptorchidism rate was identical (1.6%) whichever criterion was used. We therefore recommend that position be used as the sole criterion for diagnosing cryptorchidism. There was a clear decrease in the cryptorchidism rate with increasing birth weight. A testis that was undescended at birth was more likely to descend spontaneously by 3 months the lower its position along the normal pathway of descent. For a given position of the testis, cryptorchid babies weighing less than 2500 g had a greater chance of spontaneous descent by 3 months than larger babies. An independent effect of gestation is suggested; cryptorchid babies of less than 37 weeks' gestation were more likely to have normally descended testes at 3 months than babies of longer gestation.

Birth Weight↗

Cryptorchidism: a prospective study of 7500 consecutive male births, 1984-8. John Radcliffe Hospital Cryptorchidism Study Group.

A total of 7441 boys were examined for cryptorchidism at birth and, if present, again at 3 months of age. After excluding boys with severe congenital malformations noted at birth, the cryptorchidism rates at 3 months in babies weighing less than 2000 g, 2000-2499 g, and greater than or equal to 2500 g were 7.7%, 2.5%, and 1.41% respectively. The overall rate was 1.55%. The cryptorchidism rate at birth had increased by 35.1% and at 3 months by 92.7%, over Scorer's rates in the 1950s. Part of these increases may be attributable to differences in neonatal mortality, but the increases in babies weighing 2500 g or more of 50.2% at birth and 77.4% at 3 months are unlikely to be overestimates. At birth 1.92% of boys had bilateral cryptorchidism and 3.0% unilateral cryptorchidism. Boys with cryptorchidism at 3 months were more likely to have hypospadias, a small scrotum, and poor scrotal rugation compared with boys having normally descended testes at birth. Factors predicting descent by 3 months in babies cryptorchid at birth are birth weight, laterality and scrotal size, babies with low birth weight, bilateral cryptorchidism, and normal scrotal size being more likely to have normally descended testes by 3 months. Descent by 3 months was more likely the lower the testis along the normal pathway of descent. The orchidopexy rate at an average age of 3 years was 1.24%. This is substantially lower than in other series and lower than our estimated rate of 2.9% using Hospital In-Patient Enquiry data for England and Wales.

Birth Weight↗

[A study on cryptorchidism. II. Light and electron microscopic study of the seminiferous tubular wall in the testes of cryptorchid patients].

Morphological changes in the wall of the seminiferous tubules in the cryptorchid testes were studied using light and electron microscopy. Seventy four unilateral and bilateral cryptorchids (aged 2 to 37 years) were selected, and biopsied specimens were stained with H-E, Azan and Weigert for light microscopic observation. Twenty eight of these specimens were also examined by electron microscopy. In the undescended testes, light microscopy showed irregularity and thickening of the wall (tunica propria), and the thickened wall strongly reacted to the Azan stain. This thickening of the tunica propria was observed to begin at puberty, but was not found in the contralateral scrotal testes of the cryptorchids or in the normal testes. The wall of the normal adult testes was well stained by the Weigert stain, suggesting the presence of elastin. In the undescended testes, however, the wall was not stained in prepubertal or pubertal patients, and even after puberty the wall was stained much less than that in the contralateral scrotal testes and the normal controls. On electron microscopic observation, various ultrastructural changes were noticed in each component of the tubular wall; basement membrane, fibrous layer and cellular layer. In the undescended testes, the lamina densa of the basement membrane consisted of one layer with a serrated outer margin throughout the pre-pubertal and pubertal periods, while after puberty the lamina densa underwent marked multiple lamella formation and increased in thickness. In the fibrous layer was already noticed in the undescended testes of 5-year-old cryptorchids. The development of myoid cells in the cellular layer during puberty was observed to be delayed. The morphological changes occurring in the seminiferous tubular wall of the cryptorchid testes were believed to be related to the impaired spermatogenesis often found in cryptorchidism.

Adolescent↗

Effect of cryptorchidism on testicular histology in a naturally cryptorchid animal model.

PURPOSE: To determine the effect of naturally occurring cryptorchidism on testicular histology in both the cryptorchid and normally descended testis from birth to adulthood using the LE/ORL rat model. MATERIALS AND METHODS: Testicular histology was assessed using established morphometric measures in bilaterally descended (BD), unilaterally descended (UD), bilaterally cryptorchid (BC) and unilaterally cryptorchid (UC) testis at days 15, 22, 30, 45 and 60 of age. Testicular mass was also measured at these times. RESULTS: Changes in testicular histology in the BC and UC testes were not noted on or prior to day 30 of age. Significant changes were noted by day 45 of age and continued into adulthood at day 60 of age. There were no histological abnormalities noted in the UD and BD groups. CONCLUSIONS: Since histological changes seen in this animal model occur after the time of testicular descent (day 28 of age), we hypothesize that these changes are due to an abnormal anatomical position of the testis as opposed to an inherent testicular defect in the LE/ORL rat. This hypothesis is supported by the fact that no histological differences were noted between the scrotal testes of unilaterally cryptorchid animals and bilaterally descended control animals.

Age Factors↗

Cryptorchidism: an apparent substantial increase since 1960. John Radcliffe Hospital Cryptorchidism Study Group.

A total of 1849 boys born to mothers resident in a defined area around Oxford were examined for cryptorchidism. Those born in hospital were examined at birth and again after three months if cryptorchid at the earlier examination. The incidence of cryptorchidism at three months adjusted to the birthweight distribution of England and Wales was 1.58%. By comparison, in a very similar study conducted around 1960 the incidence was 0.96%. Hence the cryptorchidism rate had apparently increased by 65% over the two decades, which contrasted with the twofold increase in the national orchidopexy rate. The proportion of boys undergoing orchidopexy appeared consistently to be roughly twice the proportion of boys with an undescended testis at 3 months of age. The increase in cryptorchidism and disparity with the rate of orchidopexy are not easily explained and are the subjects of continuing study.

Cryptorchidism↗

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.

Carcinoma in Situ↗

[A study of cryptorchidism. I. Light and electron microscopic study of Leydig's cells in the testes of cryptorchid patients].

A morphological study of the Leydig's cells in the testes of cryptorchid patients was made by light and electron microscopy. Seventy four unilateral and bilateral cryptorchids (aged 2 to 37 years) were selected for light microscopic observation, and 28 of these specimens were also examined by electron microscopy. In 5 cases of pre-pubertal and pubertal cryptorchids, tissue specimens were biopsied after 20,000 units of HCG had been given and examined similarly. In addition, Leydig's cell density was evaluated quantitatively in the undescended and contralateral scrotal testes of 12 post-pubertal patients. This was based on the determination of the total number of Leydig's cells, Leydig's cell clusters and seminiferous tubules in the entire histologic section of each biopsy and the calculation of the following indices; mean number of Leydig's cells per tubule, mean number of Leydig's cell clusters per tubule and mean number of Leydig's cells per cluster. In addition, the number of Sertoli's cells was counted, and the ratio of Leydig's cells to Sertoli's cells was also calculated. In the undescended testes, almost no mature Leydig's cells were found by light or electron microscopy during pre-pubertal periods; and, even in puberty they were few, while immature precursor Leydig's cells were abundant. In the 5 cases treated preoperatively with HCG, even at 5 years, mature Leydig's cells were observed by light and electron microscopy. On the contrary, after puberty, not only the undescended but also the contralateral scrotal testes of the cryptorchids had more mature Leydig's cells than the normal controls. This Leydig's cell hyperplasia was also confirmed by the quantitative analysis of Leydig's cell density. In the mature Leydig's cells of the undescended testes, however, the electron microscopic observation showed marked regressive changes, in cytology especially prominent depletion of the smooth endoplasmic reticulum and frequent occurrence of specific cytoplasmic inclusion bodies. Such regressive changes as found in the cells of the undescended testes were not observed in the cells of the contralateral scrotal testes. Thus, the morphological alteration of Leydig's cells observed here suggest that the cells are in a dysfunctional condition and that the androgen production is consequently decreased in the undescended testes of cryptorchid patients.

Adolescent↗

Hypophyso-gonadal function in the cryptorchid child: differences between unilateral and bilateral cryptorchids.

In 22 normal boys, 33 unilateral and 14 bilateral cryptorchids, a gonadal function test (2000 IU of HCG im each day for three days and assays of plasma testosterone and plasma oestradiol-17beta before and after the HCG administration) as well as an LH-RH test were carried out. In 60% of the cases, both normal and cryptorchid boys, plasma oestradiol-17beta (both in basal conditions and after stimulus) were found to be less than the sensitivity (5 pg/ml) of the method, While the plasma testosterone was similar under basal conditions in the three groups of children, after HCG it was significantly lower than the mean value of the control group only in the bilateral cryptorchids. The testosterone levels, both under basal conditions and after stimulus, are correlated to bone age only in the normal boys and in the unilateral cryptorchids. There were no significant differences among the various groups for either LH and FSH both under basal conditions and after LH-RH. The LH curve area during the LH-RH test is in correlation with bone age only in the normal children.

Child↗

The epidemiology of cryptorchidism. John Radcliffe Hospital Cryptorchidism Research Group.

A total of 3,559 boys were examined for cryptorchidism over a 2-year period. At birth, 5.9% (210/3,534) had one or both testes undescended and at 3 months of age 1.61% (57/3,534) still had an undescended testis. These figures represent an increase in undescended testis of 40% at birth and 68% at 3 months when compared with figures collected in a similar study in the late 1950s. This increase in cryptorchidism still does not account for the increased number of orchiopexies being performed. Low birthweight was also found to be a risk factor for the presence of an undescended testis.

Age Factors↗

A study of cryptorchidism. III: The histochemistry of complex carbohydrates in the testes of cryptorchid patients.

The complex carbohydrates in the undescended and contralateral scrotal testes of patients with cryptorchidism, were examined by light microscopic histochemical methods, in comparison with those of normal testes. In the undescended testes, histochemical reactions for acidic and neutral complex carbohydrates were apparently weaker than in the normal testes, especially pronounced in the seminiferous tubular walls. In the germinal and supporting cells of the undescended testes, the amount of galactose residues in the complex carbohydrates decreased from the prepubertal to post-pubertal periods. Periodic acid-Schiff reaction also revealed a decrease in the glycogen content in the germinal and supporting cells of the undescended testes from pre-pubertal to post-pubertal periods.

Adolescent↗

Cryptorchidism and infertility: retrospective study of 18 post puberal patients affected with monolateral cryptorchidism.

The Authors report their experience on patients with monolateral inguinal cryptorchidism, comparing the clinical picture with the morphological pattern of both the testicular parenchima and the semen. Light and electron microscopic analysis of testicular biopsy and spermatozoa from the ejaculate have been taken into account. 4 patients out of 18 (22.2%) showed a normal spermiogram, while 14 showed a pathological spermiogram. The morphological study of the testicular parenchima showed a spectrum of lesions, most of which advanced, confirming that they are irreversible lesions of the germinal epithelium.

Adolescent↗