Human Cryptorchidism Research Articles

Exploring Testicular Descent: Recent Findings and Future Prospects in Canine Cryptorchidism.

Background Canine cryptorchidism, manifested by an abnormal testicular position, poses significant health risks and reproductive challenges in affected males. Despite a high prevalence, estimated at up to 10% in the canine population, a comprehensive understanding of its pathogenesis remains elusive. Studies in human cryptorchids and knockout mice have identified key factors involved in testicular descent, including INSL3, RXFP2 and AR. To date, only three DNA variants, found in the RXFP2, HMGA2 and KAT6A genes, have been associated with canine cryptorchidism. Summary This review briefly summarizes current knowledge on testicular descent and the factors that regulate this process, based on cryptorchidism in humans and mice. It also highlights recent findings related to canine cryptorchidism, focusing on the INSL3, HMGA2 and KAT6A genes. The most significant results are discussed, with an emphasis on the role of the epididymis in testicular descent. This report presents insights that may facilitate further research aiming to broaden our understanding of canine cryptorchidism pathogenesis. Key Messages DNA polymorphism in the KAT6A gene, associated with changes in global H3K9 acetylation, as well as the DNA methylation pattern in the INSL3 gene, suggest that further research should strongly focus on epigenetic modifications. In addition, the development of the epididymo-testicular junction and the link between cryptorchidism prevalence and dog size should be further investigated.

Functional Importance of Mini-Puberty in Spermatogenic Stem Cell Formation

Primordial germ cells nesting in the fetal testis give rise to gonocytes. The gonocytes then transform into spermatogenic stem cells (SSCs) during the neonatal period and thereafter serve as a lifetime source of spermatogenesis. Therefore, gonocyte to SSC transformation is quite an important process that supports fertility in males. During the gonocyte to SSC transformation, morphological and transcriptomic changes sequentially occur and gonocytes migrate from the center to the peripheral region of the seminiferous tubules. However, extrinsic signals which trigger the transcriptomic changes as well as the migration are not yet fully clarified. Recent studies have drawn attention to the temporal activation of the hypothalamic-pituitary-gonadal axis during the neonatal stage which occurs concurrently with SSC formation. This phenomenon is called mini-puberty, and recent studies on human cryptorchid patients as well as animal models partially support the hypothesis that mini-puberty plays pivotal roles in gonocyte-to-SSC transformation. Focusing on this point, here, we aimed to discuss the latest knowledge on the importance of mini-puberty in spermatogenesis in this review.

Evolution of Fertilization-Related Genes Provides Insights Into Reproductive Health in Natural Ascrotal Mammals

Cryptorchidism is the failure of one or both testes to descend into the bottom of the scrotum. This common congenital malformation in humans and domestic animals is the best characterized risk factor for abnormal sperm functions and infertility. However, current treatment approaches for cryptorchidism do not ensure paternity in all cases. Some lineages of mammals (such as elephants and cetaceans) have natural ascrotal testes (i.e., undescended or incompletely descended testes) and normal sperm motility and fertility, providing an opportunity to understand the genetic basis of cryptorchidism. In this study, we showed that genes associated with sperm motility and competition/fertility in ascrotal mammals experienced frequent, strong selective pressure. The fixation of specific amino acids and positive selection in ascrotal mammals could affect the physicochemical properties and functions of fertilization-related proteins. In a comparison between mammals with undescended testes and incompletely descended testes, discrepancies in genes showing evidence for adaptive evolution and in functional enrichment suggested that multiple molecular mechanisms contribute to the maintenance of fertility in the challenging testicular environment. Our findings revealed substantial heterogeneity in the divergence of fertilization-related genes between natural scrotal and ascrotal mammals and provide insight into molecular mechanisms underlying normal sperm motility and competition in natural ascrotal mammals. We provide a detailed theoretical basis for understanding the pathology of cryptorchidism from a molecular evolutionary perspective. This study may contribute to the establishment of diagnostic and therapeutic targets for sperm motility and fertility disorders due to congenital cryptorchidism in humans and domestic animals.

Aryl Hydrocarbon Receptor Activity in Human Breast Milk and Cryptorchidism. A Casecontrol Study within the Prospective Norwegian Humis Cohort

Aryl Hydrocarbon Receptor Activity in Human Breast Milk and Cryptorchidism. A Casecontrol Study within the Prospective Norwegian Humis Cohort

Rapid evolution and molecular convergence in cryptorchidism-related genes associated with inherently undescended testes in mammals

BackgroundThe mammalian testis is an important male exocrine gland and spermatozoa-producing organ that usually lies in extra-abdominal scrotums to provide a cooler environment for spermatogenesis and sperm storage. Testicles sometimes fail to descend, leading to cryptorchidism. However, certain groups of mammals possess inherently ascrotal testes (i.e. testes that do not descend completely or at all) that have the same physiological functions as completely descended scrotal testes. Although several anatomical and hormonal factors involved in testicular descent have been studied, there is still a paucity of comprehensive research on the genetic mechanisms underlying the evolution of testicular descent in mammals and how mammals with ascrotal testes maintain their reproductive health.ResultsWe performed integrative phenotypic and comparative genomic analyses of 380 cryptorchidism-related genes and found that the mammalian ascrotal testes trait is derived from an ancestral scrotal state. Rapidly evolving genes in ascrotal mammals were enriched in the Hedgehog pathway—which regulates Leydig cell differentiation and testosterone secretion—and muscle development. Moreover, some cryptorchidism-related genes in ascrotal mammals had undergone positive selection and contained specific mutations and indels. Genes harboring convergent/parallel amino acid substitutions between ascrotal mammals were enriched in GTPase functions.ConclusionsOur results suggest that the scrotal testis is an ancestral state in mammals, and the ascrotal phenotype was derived multiple times in independent lineages. In addition, the adaptive evolution of genes involved in testicular descent and the development of the gubernaculum contributed to the evolution of ascrotal testes. Accurate DNA replication, the proper segregation of genetic material, and appropriate autophagy are the potential mechanisms for maintaining physiological normality during spermatogenesis in ascrotal mammals. Furthermore, the molecular convergence of GTPases is probably a mechanism in the ascrotal testes of different mammals. This study provides novel insights into the evolution of the testis and scrotum in mammals and contributes to a better understanding of the pathogenesis of cryptorchidism in humans.

Bcl2-Associated X (BAX) Knockout in Mice Resulted in Persistence of Neonatal Testicular Germ Cells (Gonocytes)

During early testicular development, neonatal gonocytes transform into spermatogonial stem cells (SSC), and any untransformed gonocytes are thought to undergo apoptosis. In human cryptorchidism, persisting gonocytes may lead to seminoma. Using Bcl2-associated X knockout (BAXKO) mice, we investigated apoptosis in gonocyte development during mouse minipuberty. Testes from BAXKO, heterozygous (HET), and wild-type (WT) littermates were collected on postnatal days 1, 3, 6, and 9 (n = 6/group), labelled with antibodies against mouse vasa homologue (MVH, germ cell marker) or promyelocytic leukaemia zinc-factor (PLZF, SSC marker) and imaged for cell counting. Total germ cells/tubule, i.e., the number of germ cells on and off the basement membrane (BM), were counted using Image J followed by 2-way ANOVA analysis with Prism. Total PLZF+ germ cells/tubule, PLZF+ germ cells/tubule off BM, total MVH+ germ cells/tubule, and MVH+ germ cells off BM/tubule were significantly higher at day 9 in BAXKO compared to WT and HET mice (p < 0.01). In conclusion, knockout of BAX in mouse leads to gonocytes persisting at the centre of the tubules after minipuberty, which failed to migrate and transform into SSC, indicating the important role of apoptosis is to eliminate undifferentiated gonocytes during transformation. Failed apoptosis in gonocytes may be the cause of malignancy in humans with cryptorchidism.

Familial bilateral cryptorchidism is caused by recessive variants in RXFP2

BackgroundCryptorchidism or failure of testicular descent is the most common genitourinary birth defect in males. While both the insulin-like peptide 3 (INSL3) and its receptor, relaxin family peptide receptor 2...

MiR-34c disrupts spermatogonial stem cell homeostasis in cryptorchid testes by targeting Nanos2

BackgroundCryptorchidism as a common genitourinary malformation with the serious complication of male infertility draws widespread attention. With several reported miRNAs playing critical roles in spermatogonial stem cells (SSCs), we aimed to explore the fundamental function of the highly conserved miR-34c in cryptorchidism.MethodsTo explore whether miR-34c participates in spermatogenesis by regulating Nanos2, we examined the effect of overexpression and inhibition for miR-34c on Nanos2 expression in GC-1 cells. Moreover, the expression levels of miR-34c and Nanos2 with cryptorchidism in humans and mice were examined. Furthermore, the homeostasis of SSCs was evaluated through counting the number of promyelocytic leukemia zinc finger (PLZF) positive spermatogonia in murine cryptorchid testes.ResultsIn the present study, we show that miR-34c could inhibit the expression of Nanos2 in GC-1 cells. Meanwhile, miR-34c significantly decreased in both the testicular tissues of patients with cryptorchidism and surgery-induced murine model of cryptorchidism. Western blot revealed that the protein level of Nanos2 was up-regulated and showed to be negatively correlated to the expression of miR-34c in our model. The abnormal expression of miR-34c/Nanos2 disrupted the balance between SSC self-renewal and differentiation, eventually damaging the spermatogenesis of cryptorchid testes.ConclusionsThe miR-34c/Nanos2 pathway provides new insight into the mechanism of male infertility caused by cryptorchidism. Our results indicate that miR-34c may serve as a biological marker for treatment of infertility caused by cryptorchidism.

Cypermethrin exposure and effects on the reproductive male system: a literature review

The use of pesticides has become a major problem of public and environmental health in the world and especially in Brazil, which consumes tons of these compounds every year since the 50s. Among the pesticides, cypermethrin is an admittedly widely used synthetic pyrethroid due to its broad spectrum of action, resulting in its massive use in the agricultural sector. Epidemiological data show a considerable increase in the incidence of diseases in the male reproductive tract among them, the decline of sperm quality in various regions of the world, with consequent increase in demand for assisted reproduction services and increased incidences of cryptorchidism, hypospadias and testicular tumors. In recent years, researchers have shown that some pyrethroid compounds are capable of interfering with the endocrine system of animal species, including human being and therefore can be considered as endocrine disrupters. They can result in a deviation from normal homeostatic control or reproduction by interfering with the synthesis, secretion, transport, binding, action or elimination of natural hormones. It has been reported that endocrine disruptors may be responsible for the decline in sperm density and increase in hypospadias, cryptorchidism and testicular cancer in humans. In this sense, experimental studies have shown that cypermethrin acts indirectly on male gametogenesis, interfering with the synthesis of testosterone. Other disorders induced by cypermethrin are also reported, as structural changes of the seminiferous tubules, morphological changes in germ cells and sperm as well as a reduction in their count in semen. This paper aims to demonstrate aspects of endocrine disruption in the male reproductive system related to cypermethrin exposure, using data from animal studies ( in vivo ) and biological samples of human beings ( in vitro ).

The influence of hormonal treatment with beta-human chorionic gonadotropin for cryptorchidism on future fertility in rats

There have been two treatment modalities for cryptorchidism such that surgical and hormonal; the latter being highly controversial. While some authors suggest that hormonal treatment increases the number and maturation of germ cells in cryptorchid testes, others believe just the opposite. We aimed to find out the sperm counts and testicular index; briefly fertility potential of the normally descended contralateral testes in adulthood period in rats treated with Beta-HCG in early period of their lives. Three groups, each including 10 rats aged 22 days old, in which delactation and normal feeding can be started, were formed to be Group 1: Sham operated, Group 2: Experimental cryptorchidism (EC) and Group 3: Hormone-treated after experimental cryptorchidism was performed (HT-EC). Left testis was placed in the abdomen in group 2 and 3. In group 1, a sham operation was performed. The rats in EC-HT group received subcutaneous injections of 50 IU/kg Beta-HCG daily for 7 days. Right orchidectomy was performed when they reached reproductive period to evaluate fertility potential with sperm counts and testicular index. Testicular index was calculated according to the formula "testicular length × width/weight of rat". Epididymal sperm count was made with hemocytometer. We evaluated the physical characteristics and fertility potential (sperm counts) of contralateral normal testes during adulthood in rats that underwent experimental unilateral cryptorchidism during infancy. A relationship between testis weight and sperm counts were also investigated. We could not find any direct correlation of sperm count with either testicular weight or testicular index in our study. Although the rats had normal testes at birth, we found decreased sperm counts in contralateral normal testes in EC group. This suggests that unilateral cryptorchidism may cause some systemic effects that reach the other testis. Hormone treatment was not beneficial. This is comparable to Nambirajan et al. who reported histological changes and decreased spermatogenic cell count in contralateral scrotal testes in experimentally induced unilateral cryptorchidism in early period of life in rats. Heiskanen et al. reported that treatment with Beta-HCG leads to decreased total sperm counts in the future due to increased germ cell apoptosis caused by hormonal withdrawal after treatment. Cortes et al. also reported decreased number of germ cells in 1-3 year-old boys who underwent surgery after unsuccessful Beta-HCG treatment. The reasons could be delayed testicular descent or adverse effect of hormone treatment though. Our results concurred with them. Apparently, our model has failed to mimic the pathophysiologic mechanisms of congenital cryptorchidism in humans. Furthermore, we applied hormone treatment in normal rats with normally descended testes. Therefore, the "by-product" information of our study is that, unnecessary use of Beta-HCG during infancy may impair future fertility. Our study suggests that Beta-HCG treatment may decrease sperm counts and decrease the future fertility potential. We could not find any direct correlation of sperm count with either testicular weight or testicular index.

Expression of β-nerve growth factor and homeobox A10 in experimental cryptorchidism treated with exogenous nerve growth factor.

With the exception of standard inguinal orchidopexy, treatment of cryptorchidism with human chorionic gonadotropin has been performed for several years; however, its side effects have limited its application. The β‑nerve growth factor (NGF) and homeobox A10 (HoxA10) genes are closely associated with the development of the testes. To the best of our knowledge, whether exogenous NGF alters the endogenous levels of NGF and HoxA10 in cryptorchidism in rats remains to be elucidated. The aim of the present study was to evaluate the gene and protein expression of NGF and HoxA10 in experimental cryptorchidism following treatment with exogenous NGF. A unilateral mechanical cryptorchidism model in Sprague-Dawley rats was established and different concentrations of exogenous NGF were administered to observe the effects of NGF on cryptorchidism. Changes in the gene and protein expression levels of NGF and HoxA10 in the cryptorchid tissues of each group were identified using one step reverse transcription-quantitative polymerase chain reaction, in situ hybridization with digoxigenin‑labeled‑β‑NGF RNA probes, immunofluorescence and immunohistochemistry, respectively. The expression levels of NGF and HoxA10 were markedly higher in the group treated with a high dose of exogenous NGF compared with the group treated with a low dose of exogenous NGF and the group treated with human chorionic gonadotropin. These results confirmed the potential therapeutic effect of exogenous NGF in human cryptorchidism.

Mast cell numbers negatively correlate with fibrosis in cryptorchid testes

PurposeMast cells have been found to play a role in fibrotic processes in multiple organ systems and are increased in number in the testes of infertile men. We have reviewed the literature and to date have found no studies investigating the role of mast cells in fibrosis of undescended testis. We examined the expression of mast cells in human cryptorchid testes and compared mast cell expression with testicular fibrosis in these testes. MethodsTesticular biopsies from cryptorchid testis were collected over 2 years. Biopsies from 78 patients were retrospectively sectioned, stained, and reviewed for the amount of fibrosis (graded 0–3) as well as mast cell number (MCN). MCNs were quantified by tryptase staining, and the average MCN per high-powered field (HPF) was determined. Statistical analysis was performed using a one-way ANOVA with a Kruskal–Wallis test and post hoc analysis with the Dunn test when significant. ResultsLarger MCNs were significantly associated with lower fibrotic indices at the time of orchidopexy. The average MCNs were 2.06, 0.86, 0.37, and 0.58 for fibrotic indices of 0, 1, 2, and 3, respectively. MCNs were significantly higher in biopsies with a fibrotic index of 0 than all other groups (p < 0.05). ConclusionMast cell expression correlates inversely with testicular fibrosis in cryptorchid testes. Further studies correlating mast cell expression with testicular function in boys with cryptorchidism are warranted.

Hoxa-11 maintains cell proliferation in the mouse gubernaculum to facilitate testicular descent

IntroductionThe gubernaculum is a structure vital for guiding testicular descent. The Homeobox gene, Hoxa-11, is involved in patterning embryonic structures and is necessary for gubernacular development, as Hoxa-11 knock-out mice exhibit abnormal gubernacula and undescended testes. We aimed to elucidate how testicular descent fails by examining cell proliferation and androgen receptor (AR) expression in Hoxa-11 KO mice gubernacula. MethodsPostnatal day 2 wild type (n=6) and Hoxa-11 KO mice (n=6), were prepared for immunohistochemistry and confocal microscopy using antibodies against androgen receptor, slow skeletal myosin (My32), and Ki67, a marker of cell proliferation. ResultsThe gubernacula of Hoxa-11 KO mice were hypocellular compared with WT. AR was present in the gubernaculum and abutting inguinal fat pad in both WT and Hoxa-11 KO with no difference in expression. Slow skeletal myosin was present in a clear ‘swirl’ in the growth centre of WT animals which was absent in the Hoxa-11 KO mice. Ki67, expressed in the growth centre and cremaster muscle in WT, was greatly decreased in Hoxa-11 KO. ConclusionHoxa-11 may regulate fibroblast proliferation in the gubernaculum, as it does in human uterosacral ligaments, allowing formation of the 'growth centre' within the bulb and facilitating myogenesis and elongation to the scrotum. Polymorphisms in Hoxa-11 may contribute to the aetiology of human cryptorchidism.

Sertoli cell dedifferentiation in human cryptorchidism and gender reassignment shows similarities between fetal environmental and adult medical treatment estrogen and antiandrogen exposure

Studies over the last years show an increase in testicular cancer, hypospadias and cryptorchidism in industrial countries, leading to the concept of testicular dysgenesis syndrome (TDS). It is hypothesized that TDS is caused by estrogen and antiandrogen exposure during fetal life, accompanied by incomplete maturation of testicular Sertoli cells (SC). However, it is not known if SC disruption is a primary cause or a response to fetal Leydig cell testosterone production changes.To determine if SC differentiation is directly affected by estrogens, we compared SC maturation between adult gender reassignment cases exposed to estrogen and antiandrogen therapy, and those of typical TDS in adult cryptorchidism.We found similar expression of immature SC markers M2A antigen, inhibin bodies and Anti Mullerian Hormone, and the absence of maturation marker androgen receptor in SC of both types of patients. These data supports the occurrence of true SC dedifferentiation caused by estrogen exposure in adult humans. Our data also suggests that SC maturation is directly disrupted in TDS.

Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti‐androgenic in the rat foetal testis

More than half the pregnant women in the Western world report taking mild analgesics. These pharmaceutical compounds have been associated with congenital cryptorchidism in humans, the best-known risk factor for low semen quality and testicular germ cell cancer. Furthermore, some of these mild analgesics exert potent anti-androgenic effects in the male rat and several endocrine-disrupting compounds, known to alter masculinization, have also been shown to be potent inhibitors of prostaglandin (PG) synthesis similar to mild analgesics. Using a 3-day ex vivo organotypic model system based on gestational day 14.5 rat testes, we herein show that testosterone production was inhibited by paracetamol, at doses of 0.1 μm to 100 μm. Similar results were obtained for aspirin (1-100 μm) and indomethacin (10 μm). The production of the other Leydig cell hormone, Insl3, was not disrupted by exposure to paracetamol. Investigations of the gross anatomy of the testis as well as Leydig cells number and rate of gonocyte apoptosis after the 3 days of ex vivo differentiation showed no significant effect of the analgesics tested compared with controls. These data indicate therefore that mild analgesics specifically inhibit testosterone production in rat foetal testes in vitro and that these compounds had no effect on gonocyte survival. Parallel determinations of prostaglandin D2 (PGD2) production indicated that the effects of paracetamol and aspirin on PGD2 and testosterone were not connected, whereas the effects of indomethacin were correlated. We conclude that mild analgesics exert direct and specific anti-androgenic effects in rat foetal testis in our experimental setup and that the mechanism of action is probably uncoupled from the inhibition of PG synthesis.

1375 FUNCTIONAL ANALYSIS OF SPERMATOGONIAL STEM CELLS IN CRYPTORCHIDISM USING EEF1A1 AND TPT1 GENE EXPRESSION AS INDEXES OF CELL DIFFERENTIATION

You have accessJournal of UrologyPediatrics: Andrology - Cryptorchidism & Varicoceles1 Apr 20121375 FUNCTIONAL ANALYSIS OF SPERMATOGONIAL STEM CELLS IN CRYPTORCHIDISM USING EEF1A1 AND TPT1 GENE EXPRESSION AS INDEXES OF CELL DIFFERENTIATION Kentaro Mizuno, Yoshiyuki Kojima, Hideyuki Kamisawa, Satoshi Kurokawa, Makoto Imura, Yoshinobu Moritoki, Hidenori Nishio, Yasuhiro Shibata, Akihiro Nakane, Toshiki Kato, Tetsuji Maruyama, Yutaro Hayashi, and Kenjiro Kohri Kentaro MizunoKentaro Mizuno Nagoya, Japan More articles by this author , Yoshiyuki KojimaYoshiyuki Kojima Nagoya, Japan More articles by this author , Hideyuki KamisawaHideyuki Kamisawa Nagoya, Japan More articles by this author , Satoshi KurokawaSatoshi Kurokawa Nagoya, Japan More articles by this author , Makoto ImuraMakoto Imura Nagoya, Japan More articles by this author , Yoshinobu MoritokiYoshinobu Moritoki Nagoya, Japan More articles by this author , Hidenori NishioHidenori Nishio Nagoya, Japan More articles by this author , Yasuhiro ShibataYasuhiro Shibata Nagoya, Japan More articles by this author , Akihiro NakaneAkihiro Nakane Nagoya, Japan More articles by this author , Toshiki KatoToshiki Kato Nagoya, Japan More articles by this author , Tetsuji MaruyamaTetsuji Maruyama Nagoya, Japan More articles by this author , Yutaro HayashiYutaro Hayashi Nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri Nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1759AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It has been suggested that future fertility is affected by the number or function of spermatogonia derived from spermatogonial stem cells in cryptorchid testes. We have previously found that EEF1A1 and TPT1 genes are differentially expressed in human cryptorchid testes and believe that these genes reflect the stage of spermatogonia development. In this context, we have previously evaluated the expression of these genes in boys aged 1–5 years, but expression in other age groups remains unclear. To elucidate the chronological differentiation in spermatogonia, we assessed cryptorchid testes by histological and molecular biological examination. METHODS We used specimens derived from testicular biopsy during orchiopexy for cryptorchidism (88 cases, 109 testes) from October 2001 to April 2011. The patients were divided into 2 groups:(1) early orchiopexy (before 1 year of age) and (2) late orchiopexy (after 6 years of age). Histological assessment using light microscopy and molecular biological assessment using the expression levels of EEF1A1 and TPT1 genes by real-time RT-PCR were performed. Relative expression values of these genes were calculated and compared with those from age-matched descended testes. RESULTS The number of spermatogonia per tubule was significantly higher in the early orchiopexy group (p < 0.005). Relative expression values of the EEF1A1 gene were not significantly different between groups, whereas those of the TPT1 gene in the late orchiopexy group were significantly lower than those of age-matched descended testes (p < 0.005). CONCLUSIONS It has been suggested that leaving cryptorchid testes until school age induces testicular fibrillization and loss of spermatogonia. Combined with our previous results, it can be seen that the EEF1A1 gene is highly expressed until 6 years of age and is subsequently equally expressed in cryptorchid testes and descended testes. In contrast, expression of the TPT1 gene was lower in cryptorchid testes than descended testes after 6 years of age. The TPT1 gene was expressed in spermatogonia and was associated with an undifferentiated state of these cells, suggesting that spermatogonia could not maintain stemness in cryptorchid testes. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e558-e559 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kentaro Mizuno Nagoya, Japan More articles by this author Yoshiyuki Kojima Nagoya, Japan More articles by this author Hideyuki Kamisawa Nagoya, Japan More articles by this author Satoshi Kurokawa Nagoya, Japan More articles by this author Makoto Imura Nagoya, Japan More articles by this author Yoshinobu Moritoki Nagoya, Japan More articles by this author Hidenori Nishio Nagoya, Japan More articles by this author Yasuhiro Shibata Nagoya, Japan More articles by this author Akihiro Nakane Nagoya, Japan More articles by this author Toshiki Kato Nagoya, Japan More articles by this author Tetsuji Maruyama Nagoya, Japan More articles by this author Yutaro Hayashi Nagoya, Japan More articles by this author Kenjiro Kohri Nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Attenuation of Spermatogonial Stem Cell Activity in Cryptorchid Testes

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.

Testicular descent: INSL3, testosterone, genes and the intrauterine milieu

Complete testicular descent is a sign of, and a prerequisite for, normal testicular function in adult life. The process of testis descent is dependent on gubernacular growth and reorganization, which is regulated by the Leydig cell hormones insulin-like peptide 3 (INSL3) and testosterone. Investigation of the role of INSL3 and its receptor, relaxin-family peptide receptor 2 (RXFP2), has contributed substantially to our understanding of the hormonal control of testicular descent. Cryptorchidism is a common congenital malformation, which is seen in 2-9% of newborn boys, and confers an increased risk of infertility and testicular cancer in adulthood. Although some cases of isolated cryptorchidism in humans can be ascribed to known genetic defects, such as mutations in INSL3 or RXFP2, the cause of cryptorchidism remains unknown in most patients. Several animal and human studies are currently underway to test the hypothesis that in utero factors, including environmental and maternal lifestyle factors, may be involved in the etiology of cryptorchidism. Overall, the etiology of isolated cryptorchidism seems to be complex and multifactorial, involving both genetic and nongenetic components.

The antiandrogen flutamide perturbs inguinoscrotal testicular descent in the rat and suggests a link with mammary development

Aim Inadequate androgen activity is a likely cause of cryptorchidism in humans, affecting inguinoscrotal testicular descent. Flutamide, a nonsteroidal antiandrogen, produces cryptorchidism in rats. We aimed to determine the anatomical and histologic effects of flutamide. Methods Time-mated Sprague-Dawley female rats were injected subcutaneously with flutamide (75 mg/kg in sunflower oil) on days 16 to 19 of pregnancy. Embryonic (E) and postnatal (P) male offspring were collected (E16, E19, P0, P2, P4, P8) in control and flutamide-treated groups (n = 5-10). Samples were fixed in 4% paraformaldehyde. Five-micrometer-thick sections were prepared for hematoxylin and eosin, trichrome and immunohistochemical stains (Desmin, TuJ1, Ki67). This identified muscle and neural cells and areas of cell proliferation. Results Postnatally, the gubernaculum in flutamide-treated rats had more mesenchyme and muscle than controls. Gubernacular eversion failed, and mammary tissue persisted around the gubernaculum in flutamide-treated rats. Flutamide had no effect on embryonic gubernacular anatomy and histology. Conclusions Prenatal androgens altered postnatal gubernacular anatomy and histology in the postnatal period. Our findings indicate that the failure of gubernacular differentiation and migration may be because of the ongoing presence of mammary tissue in the region of the external inguinal ring.

Electron microscopic study of interstitial cells in cryptorchid human testes. I: Interstitial cells in prepubertal age.

In order to establish the ultrastructural features of Leydig cells 50 biopsies or prepubertal human cryptorchid testes have been examined. Light and electron microscopic observations reveal the presence of two types of interstitial cells distinguishable on the basis of the peculiar ultrastructural characteristic of the nucleus and cytoplasm. In our opinion these two types of interstitial cells seem to represent different stages of cell differentiation. There are fibroblast-like cells and cells corresponding to Leydig cells. From our observations it may be inferred that the fibroblast-like cells are the precursor cells of the Leydig cells.