Cryptorchidie et infertilité masculine

Cryptorchidism is one of the various forms of testicular maldescent. Cryptorchidism is still reported to have discrepant effects upon the exocrine function of the male gonade. Besides some new information about epidemiology and risck factors associated with cryptorchidism, data from the literature are reviewed concerning spermatogenesis, fatherhood and infertility in men with a history of cryptorchidism. The discrepancy of the results is such important that only prospective and multicentric studies involving various experts seem to be appropriate to approach the complex problems arising from the maldescended testis.     

Cryptorchidie de l’enfant: syndrome ou symptôme?

Cryptorchidism is a frequent disease of children whose management remains controversial. Clinical diagnosis of cryptorchidism must assess the permanent location of the testis outside scrotum and must look for associated malformations. Endocrine investigation should include an evaluation of basal plasma testosterone and after an HCG stimulation test. Development of cryptorchidism is due to anatomical, histological and endocrine abnormalities. Medical treatment should be realised as early as possible. If testis descent does not occur, orchidopexy must be performed. Long-term effects of cryptorchidism are defined by infertility and testis cancer.     

Glycosylation pattern in the appendix testis in children with cryptorchidism

In humans, at about week 6, sex cords develop within the forming testes. Testes normally descend to the scrotum; cryptorchidism occurs when one or two testes do not descend to scrotum and in some case are accompanied by the appendix testis. The appendix testis is a small sessile or polypoid structure located at the antero superior pole of the testis, adjacent to the head of the epididymis. Glycans can be involved in development of the appendix testis and cryptorchidism. In this work, lectin histochemistry was used to evaluate glycans expression in appendix testis in children with cryptorchidism. Our results showed that lectin from Lens culinaris, Ulex europaeus I., Canavalia ensiformis, Artocarpus integrifolia, Glycine max, and Griffonia simplicifolia recognizes epithelial and estromal cells. Not interaction was observed with lectin from Amaranthus leucocarpus, while lectin from Dolichus biflorus lectin only recognizes epithelial cells. Our results suggest that O-glycans linked in some glycoproteins represent important elements in appendix testis development.     

Down-regulation of steroidogenic cytochrome P450XVII in cryptorchid rat testes

The objective of the present study was to investigate the regulation of a key component of testicular androgen biosynthesis, i.e. the cytochrome P450XVII of the steroid-17 alpha-monooxygenase/C17,20-lyase, after surgical induction of bilateral cryptorchidism in vivo. Seven days after induction of cryptorchidism, P450XVII concentrations are diminished (as compared to sham-operated controls) by 64% in isolated purified Leydig cells but only by 44% in the total Leydig cell compartment of the testis, since the Leydig cell yield from cryptorchid testes is by 53% higher than that from control testes. Using microsomal suspensions prepared from testicular homogenates, P450XVII content per testis equivalent is found to be decreased by 36% seven days after incubation of cryptorchidism, whereas the P450XVII concentration per gram testis is not changed due to testicular involution. Fourteen days after induction of cryptorchidism, the induction of the Leydig cell system appears to superimpose on the down-regulation of P450XVII. The study demonstrates both a strong sensitivity of P450XVII to short-term elevation of testicular temperature and a differentiation between effects of cryptorchidism on total testicular content and specific cellular and subcellular concentration of this steroidogenic protein.     

Anomalies postnatales du développement de la spermatogenèse associées aux troubles de la migration testiculaire

Cryptorchidism, a non-descended testis in its physiological intrascrotal location, is one of the most frequent congenital anomalies of the male genital system. The mechanisms of the normal descent of the testis are still unclear. Several etiological hypotheses have been proposed for cryptorchidism. Cryptorchidism is associated with a greater risk of testis cancer, and is also a cause of impairment in sperm parameters and fertility in the adult age. In this article, we review the cellular and hormonal events occurring from birth to puberty in isolated cases of congenital cryptorchidism that will later, in adulthood, alter both spermatogenesis and fertility.     

GLYCOSYLATION PATTERN IN THE APPENDIX TESTIS IN CHILDREN WITH CRYPTORCHIDISM

In humans, at about week 6, sex cords develop within the forming testes. Testes normally descend to the scrotum; cryptorchidism occurs when one or two testes do not descend to scrotum and in some case are accompanied by the appendix testis. The appendix testis is a small sessile or polypoid structure located at the antero superior pole of the testis, adjacent to the head of the epididymis. Glycans can be involved in development of the appendix testis and cryptorchidism. In this work, lectin histochemistry was used to evaluate glycans expression in appendix testis in children with cryptorchidism. Our results showed that lectin from Lens culinaris, Ulex europaeus I., Canavalia ensiformis, Artocarpus integrifolia, Glycine max, and Griffonia simplicifolia recognizes epithelial and estromal cells. Not interaction was observed with lectin from Amaranthus leucocarpus, while lectin from Dolichus biflorus lectin only recognizes epithelial cells. Our results suggest that O-glycans linked in some glycoproteins represent important elements in appendix testis development.     

Effects of cryptorchidism and orchidopexy on deoxyribonucleoside-activated nucleotidase (DAN) in the rat testis

1. Unilateral cryptorchidism was associated with an increase in specific DAN activity in the abdominal testis of adult rats. 2. In the scrotal, immature testis, there was an age-dependent decrease in specific DAN activity similar to that normally seen in rats. This decrease was less pronounced in the abdominal testis of unilaterally cryptorchid rats. 3. Total DAN activity in the abdominal testis showed a decrease in both immature and adult rats, when compared to that of the scrotal testis. 4. Orchidopexy following cryptorchidism in adult rats, resulted in complete restoration of DAN activity in spite of poor recovery of spermatogenesis.     

Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer.

Two hundred and fifty biopsy specimens from the contralateral testis in patients with unilateral germinal testicular cancer were analysed by light microscopy for carcinoma-in-situ changes. Changes were found in 13 (5.2%) patients. One-third of patients with an atrophic contralateral testis (volume less than or equal to 12 ml) and one-fifth of patients with a history of cryptorchidism had changes in the remaining testis. In the present series 85% of cases with carcinoma-in-situ changes would have been diagnosed if the one-fifth of the patients having an atrophic testis or a history of cryptorchidism or both had been screened. Since the natural course of carcinoma in situ in the contralateral testis of patients with germinal testicular cancer has not been established, the patients are being re-evaluated frequently. To date two patients with carcinoma in situ have developed a second cancer.     

Cryptorchidie et température testiculaire

The testis migrates to a scrotal location before birth. This physiological descent is associated with a reduction in the temperature of the testicular environment since the temperature of the scrotal cavity is lower than that of the body one. This leads to the etablishment of a themperature gradient between the testis and the body which already exists in prepubertal boys. In cases of testicular maldescent (cryptorchidism), the temperature of the testis in its cryptorchid location is much higher than that of the normally descended contrlateral testis. However, there are no data obtained from human studies to establish wether the increased temperature of a cryptorchid testis is responsible for the spermatogenic perturbations typically observed. Nor do we know wether the relocation of a cryptorchid testis to the scrotum permits re-establishment of a normal testicular temperature. Adult men with a history of cryptorchidism constitute about 10% of infertile men, and among these previously cryptorchid infertile men 45% have an abnormally elevated scrotal temperature. This abnormal increase in scrotal temperature is a negative risk factor for fertility: these men have smaller testicular volumes, a more severely impaired spermatogenesis and a higher prevalence of primary infertility than previously cryptorchid infertile than previously cryptorchid infertile men with normal scrotal temperature. However, data provided until now do not allow to know whether elevated temperature is due to the decreased testicular size (hypotrophy) or is a consequence of cryptorchidism per se.     

Germ cell death and their removal during initial stages of testicular ischemia and cryptorchidism: a comparative analysis

Germ cell death and their removal from the seminiferous epithelium are common in the affected testis in conditions of unilateral ischemia or cryptorchidism; the similarities and differences, however, have not been studied between these two conditions. The present study was designed to examine the severity of the effect on testicular germ cells during the initial stages of both ischemia and cryptorchidism, which have significant implications on the restoration of fertility following surgical repair. Complete absence of spermatids was observed following 12 hr of ischemia as compared to 7 days of cryptorchidism. Germ cell removal in either case was in the direction of lumen to basement membrane leaving only a single layer of cells by 24 hr of unilateral ischemia as compared to 15 days of cryptorchidism. Levels of intratesticular testosterone was found lower in cryptorchidism (7 days) but not in ischemia till 24 hrs. Giant cells frequently observed in cryptorchid testis were absent in the ischemic seminiferous epithelium. There was a gradual increase in the number of apoptotic and non-viable cells; the latter was more than 95% by 24 hr of ischemia. In contrast, approximately 85% testicular cells were nonviable till 15 days of cryptorchidism. The 1c peak representing the population of haploid cells was significantly reduced in cryptorchidism (7 days), while the peak was completely abolished by 24 hr of ischemia. Rise in the levels of oxidative stress in the affected testis was observed identically during the initial stages. These findings indicate that coupled with the rise in tissue oxidative stress, the number of apoptotic/nonviable germ cells was alarmingly high (> 80%) by 15 days of cryptochidism or 24 hr of ischemia. Restoration of complete spermatogenesis following surgical repair may not be possible in such cases because of these acute adverse effects.     

Morphologic study of the testes from spontaneous unilateral and bilateral abdominal cryptorchid boars

Macroscopical and histological characteristics were examined in both testes from three healthy boars, three boars with unilateral abdominal cryptorchidism on the right side, and three boars with bilateral abdominal cryptorchidism. Abdominal cryptorchidism, unilateral and bilateral, provoked a significant decrease of the weight and volume of the ectopic testes. The scrotal testis of the unilateral cryptorchid boars showed an increase in its volume and weight. Cryptorchidism also induced abnormalities in the histological structure of seminiferous tubules, lamina propria, and interstitial tissue of the abdominal testes. The number of seminiferous tubules decreased; the seminiferous epithelium was constituted by few spermatogonia with an atypical pattern and by abnormal Sertoli cells. The lamina propria showed a variable degree of thickening and collagenization. The interstitial tissue was very developed but displayed a decrease in the Leydig cell population. These abnormalities were more critical in bilateral cryptorchidism than in unilateral cryptorchidism. The scrotal testis of the unilateral cryptorchid boars showed normal appearance, but a decrease of the number of seminiferous tubules was observed. Moreover, the seminiferous tubules showed impaired spermatid maturation. The alterations observed in the abdominal testes of the unilateral and bilateral cryptorchid boars were attributed to defective proliferation and differentiation of Sertoli cells and Leydig cells. The anomalies in the scrotal testis of the unilateral cryptorchid boars were due to disturbances in the Sertoli cell activity.     

Cryptorchidism in North American cattle: breed predisposition and clinical findings

The authors analyzed data collected over 26 years from 143 cryptorchid bulls admitted to 23 North American veterinary schools. Breed was found to be a risk factor. The medical records of 41 cryptorchid cattle were also obtained, and the physical examination findings, method of diagnosis, and surgical management were recorded. Polled Hereford and Shorthorn cattle were at significantly greater risk for cryptorchidism; however, polled cattle were not at an increased risk for cryptorchidism. Cryptorchidism was most commonly diagnosed by external palpation of the superficial inguinal rings and by palpation per rectum. Unilateral cryptorchidism appears to be more common than bilateral cryptorchidism. The incidence of cryptorchidism was 69% for the left testis and 31% for the right testis. Sixty-six percent of the retained testes were located in the inguinal canal. Cryptorchidectomy was performed through an inguinal, paramedian or flank approach in 26 bulls. Cryptorchidism appears to be rare in bovine bulls admitted to North American veterinary schools, with 1.7 cases per 1,000 bull admissions. We suggest that cryptorchidism be considered an inherited trait in the Shorthorn and Polled Hereford breeds.     

Expression of Hsf1, Hsf2, and Phlda1 in cells undergoing cryptorchid-induced apoptosis in rat testes

Surgery‐induced cryptorchidism, in which the testes are prevented from descending into the scrotal sac, results in testicular germ cell death, and it is commonly used as an experimental tool in the study of spermatogenesis. However, the molecular events underlying the activation of germ cell death remain poorly understood. In the present study, we investigate selective cell loss from cryptorchid rat testis by using DNA flow cytometry and by determining protein and mRNA expression of Hsf1, Hsf2, and Phlda1. The hypo‐haploid cell fraction is significantly decreased as early as 3 days after surgical induction of cryptorchidism (from 42.01 ± 5.74% to 15.98 ± 3.88%), followed by a significant decrease in the haploid cell fraction at Day 7. At the latter time point, an apoptotic peak of spermatocytes appears in DNA histograms just before the tetraploid peak; the percentage of aneuploid cells between diploid and tetraploid rises as high as 14.05 ± 2.98% of the total cells in 7‐day cryptorchid testis, suggesting that a large number of spermatocytes are undergoing apoptosis. The expression of Phlda1 mRNA is significantly elevated 3 days after induction of cryptorchidism. After 7 days of cryptorchidism, Hsf1 and Phlda1 are strongly expressed in the nucleus and cytoplasm, respectively, of primary spermatocytes. Numerous apoptotic spermatocytes are also observed at this time point. These results suggest that the Hsf1/Phlda1 pathway plays an important role in the apoptosis of primary spermatocytes in cryptorchid testis. We present evidence suggesting that Hsf2 is also involved in germ cell removal in cryptorchid testis. Mol. Reprod. Dev. 78:283–291, 2011. © 2011 Wiley‐Liss, Inc.     

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.     

Impaired detoxification of reactive oxygen and consequent oxidative stress in experimentally cryptorchid rat testis.

The effect of experimental cryptorchidism on the level of oxidative stress and antioxidant functions in rat testis was studied. Adult male Sprague-Dawley rats were rendered unilaterally cryptorchid (by suturing one testis to the abdominal wall) and killed 1, 3, or 7 days after the operation. As an indicator of oxidative stress, lipid peroxidation was measured by the diene conjugation method in testis homogenates. The activities of the antioxidant enzymes were determined either in the 10,000 x g supernatant fraction (glutathione [GSH] peroxidase, GSH transferase, hexose monophosphate shunt) or in crude testis homogenates (superoxide dismutase, catalase). An expected reduction (48%) in weight of the abdominal testes was evident by postoperative Day 7. The catalytic activities per testis of superoxide dismutase (Cu/Zn form) and catalase were found to decrease in cryptorchidism. The effect was seen on the first postoperative day and was most profound on Day 7 after surgery. The principal antioxidant enzyme, superoxide dismutase, was most sensitive to cryptorchidism, the activity in the abdominal testes being 74% or 85% (per gram of tissue or per whole testis, respectively; p less than 0.01). After impairment of the reactive oxygen detoxifying capacity, lipid peroxidation was increased in the abdominal testis by 46% (p less than 0.01) on postoperative Day 7. Slight concomitant increases were detected in the activities of GSH-peroxidase (p less than 0.01), GSH-transferase (p less than 0.001), and the hexose monophosphate shunt (p less than 0.001). This effect was seen only when calculated per gram of tissue, not per whole testis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temporal changes in rat Leydig cell function after the induction of bilateral cryptorchidism

Adult rats were made bilaterally cryptorchid and studied at intervals of 3, 7, 14 or 21 days to study temporal changes in Leydig cell function. Serum FSH and LH levels were measured and the cross-sectional area of the Leydig cells assessed by morphometry. The function of the Leydig cells was judged by the binding of 125I-labelled hCG to testicular tissue in vitro and the testosterone response of the testis to hCG stimulation in vitro. By 3 days after cryptorchidism, the binding of labelled hCG to testicular tissue was significantly decreased compared to that of controls, but the testes were able to respond to hCG stimulation in vitro. At 7, 14 and 21 days after cryptorchidism, an enhanced testosterone response was observed and the size of the Leydig cells was significantly greater than that of the controls, which indicated increased secretory activity by the cryptorchid testis. Although serum FSH levels were significantly elevated after 3 days of cryptorchidism, serum LH levels did not rise until 7 days, thereby suggesting that the loss of receptors is unlikely to result from down-regulation by LH. The reduced testosterone response of the cryptorchid testis in vivo to low doses of hCG and the enhanced response at high doses are probably related to the reduced blood flow to the cryptorchid testis and the decreased sensitivity of the Leydig cells induced by LH/hCG receptor loss.     

A comparison of Leydig cell function after unilateral and bilateral cryptorchidism and efferent-duct-ligation

Surgical induction of cryptorchidism or ligation of the efferent ducts disrupts spermatogenesis. The response of Leydig cells to disrupted gametogenesis was studied in vitro in tissue and collagenase dispersed Leydig cells obtained from the testes of rats that were made unilaterally or bilaterally cryptorchid or had been efferent-duct-ligated. Four wks after surgery, androgen secretion per mg of tissue or per Leydig cell in response to maximal luteinizing hormone (LH) stimulation was greater in tissue from damaged than from sham-operated testes. It was concluded that disruption of spermatogenesis resulted in Leydig cells that were hyperresponsive to LH stimulation in vitro. Unilateral lesions produced different responsiveness of Leydig cells from the testes ipsilateral and contralateral to the lesion, supporting the hypothesis that intragonadal modulation of Leydig cells function occurs when the function of seminiferous tubules is impaired. Stimulated androgen production of Leydig cells from the contralateral nonligated testis did not differ from that of the sham-operated controls. With unilateral cryptorchidism, which is accompanied by an increase in the temperature of the operated testis, Leydig cells from the scrotal testis were also hyperresponsive compared to those from sham-operated controls. This suggests a possible intergonadal influence of aspermatogenesis caused by cryptorchidism.     

一种新的大鼠隐睾模型的建立

目的改善大鼠隐睾模型的制作方法,提高隐睾模型的质量,并对新模型的稳定性进行研究。方法28只大鼠随机分为对照组（ctrl）和模型组（modl）采用模拟失重大鼠模型,对大鼠进行3周尾部悬吊进行造模,随后模型组大鼠解悬吊恢复8周观察该模型的稳定性。结果经过3周的尾部悬吊,模型组所有大鼠睾丸均滑入腹腔,同时和对照组相比,睾丸和附睾的重量出现极显著的降低（P〈0.01）。HE染色发现对照组大鼠睾丸的生精小管结构排列紊乱,精原细胞消失,附睾尾中成熟精子消失。经过8周的恢复,大鼠的睾丸及附睾仍未恢复到正常水平（P〈0.01）,HE染色显示其生精小管结构和精原细胞数量并未出现明显的改善。结论尾吊法所建立的大鼠隐睾模型效果稳定,可以有效模拟大鼠隐睾时的睾丸温度变化情况,同时对大鼠的伤害较小,操作比较简单。     

Characterization of the semen quality of postpuberal boars with spontaneous unilateral abdominal cryptorchidism on the right side.

In recent studies, we found that the ectopic testis from postpuberal boars with unilateral abdominal cryptorchidism does not produce sperm. Therefore, in these males, the seminal characteristics can be used as indicators of the activity of the scrotal testis and its epididymis and also the accessory glands. The semen quality (ejaculate volume, cell-rich fraction volume, sperm concentration, sperm vitality, sperm motility, sperm morphology and cephalic stability of spermatozoa) was evaluated in healthy postpuberal boars and in postpuberal boars with unilateral abdominal cryptorchidism on the right side. In comparison with the healthy boars, the unilateral abdominal cryptorchid boars showed a significant decrease of the ejaculate volume, sperm concentration and sperm motility. The low sperm concentration indicated that unilateral abdominal cryptorchidism severely impairs the sperm production of the scrotal testis. The decrease of ejaculate volume was attributed to an abnormal activity of the accessory glands. The alterations in sperm motility develop as a result of dysfunctions in the epididymal epithelium and/or the accessory glands. The sperm vitality, sperm morphology and cephalic stability of spermatozoa maintained normal values; therefore, at testicular level, despite the low sperm production, the germ cell differentiation is not disturbed. At epididymal level, the morphological maturation of spermatozoa is not altered.     

Cryptorchidism: an indicator of testicular dysgenesis?

Cryptorchidism is a common ailment of new-born boys, affecting 1–9% of full term boys at birth. Cryptorchidism has been associated with an increased risk of testicular cancer and reduced fertility. Aetiology of cryptorchidism remains obscure in most cases. Familial occurrence suggests a heritable susceptibility to cryptorchidism; however, seasonal variation in the incidence of cryptorchidism suggests that environmental factors also contribute. Testicular descent is characterised by androgen-dependent regression of cranial suspensory ligament and androgen + insulin-like hormone 3 (Insl3)-dependent gubernacular outgrowth. Even though hormonal defects are rarely detected in patients, both hypo-and hypergonadotropic hormonal patterns have been associated with cryptorchidism. Moreover, cryptorchid boys have significantly reduced serum androgen bioactivity at 3 months of age when normal boys have a strong surge of reproductive hormones. Defects in Insl3 action cause cryptorchidism in male mice, and over-expression in female mice causes ovarian descent. Defects in leucine-rich repeat-containing G-protein-coupled receptor 8/G-protein-coupled receptor affecting testis descent (LGR8/GREAT), the receptor for Insl3, manifest the same phenotype as Insl3 knockout mutants. Even though mutations found in Insl3 and LGR8/GREAT genes are not a common cause of cryptorchidism in patients, it remains to be resolved whether low Insl3 levels during development are associated with cryptorchidism. Cryptorchidism may reflect foetal testicular dysgenesis that may later manifest as subfertility or testicular cancer.This work was supported by the Turku University Central Hospital, the Academy of Finland and the European Commission (contracts BMH4-CT96-0314, QLK4-CT1999-01422, QLK4-CT2001-00269 and QLK4-CT2002-00603).