Systematic comparison of the male reproductive tract in fetal and adult Wistar rats exposed to DBP and DINP in utero during the masculinisation programming window.

This study investigates possible effects of in utero exposure of rats to a low dose (125 mg/kg bw/day) and a high dose (750 mg/kg bw/day) of Diisononyl phthalate (DINP) during the masculinisation programming window (MPW) which is embryonic days 15.5-18.5 (e15.5 - e18.5). Dibutyl phthalate (DBP) was used at a high dose level (750 mg/kg bw/day) as an established positive control substance for anti-androgenic effects on the developing male reproductive tract. We focussed on the MPW and measured a multitude of biological endpoints at various life stages and applied state of the art histopathology staining techniques to refine the characterization of potential changes to the testis, beyond what is currently available with DINP. If DINP can mediate testicular dysgenesis (TDS) disorders, this exposure window would be sufficient to induce androgen impacts and alter male reproductive tract development as shown earlier in this validated experimental model with DBP. Overall, the results of this systematic comparison provide convincing evidence on the differences between the effects occurring with DBP and DINP. In contrast to what was seen with DBP, DINP did not cause cryptorchidism or hypospadias, had no effect on anogenital distance/anogenital index (AGD/AGi) and Leydig cell aggregates on e17.5 and e21.5 did not increase. With DINP no reduction of intratesticular testosterone, no effects on sperm motility and sperm count and no effect on adult testosterone or luteinizing hormone (LH) levels were seen. Our results demonstrate that DINP does not cause the adverse reproductive effects known to occur with DBP, a well-established endocrine disruptor.

Expansion of the renal capsular stroma, ureteric bud branching defects and cryptorchidism in mice with Wilms tumor 1 gene deletion in the stromal compartment of the developing kidney.

Development of the mammalian kidney is orchestrated by reciprocal interactions of stromal and nephrogenic mesenchymal cells with the ureteric bud epithelium. Previous work showed that the transcription factor Wilms tumor 1 (WT1) acts in the nephrogenic lineage to maintain precursor cells, to drive the epithelial transition of aggregating precursors into a renal vesicle and to specify and maintain the podocyte fate. However, WT1 is expressed not only in the nephrogenic lineage but also transiently in stromal progenitors in the renal cortex. Here we report that specific deletion of Wt1 in the stromal lineage using the Foxd1cre driver line results at birth in cryptorchidism and hypoplastic kidneys that harbour fewer and enlarged ureteric bud tips and display an expansion of capsular stroma into the cortical region. In vivo and ex vivo analysis at earlier stages revealed that stromal loss of Wt1 reduces stromal proliferation, and delays and alters branching morphogenesis, resulting in a variant architecture of the collecting duct tree with an increase of single at the expense of bifurcated ureteric bud tips. Molecular analysis identified a transient reduction of Aldh1a2 expression and of retinoic acid signalling activity in stromal progenitors, and of Ret in ureteric bud tips. Administration of retinoic acid partly rescued the branching defects of mutant kidneys in culture. We propose that WT1 maintains retinoic acid signalling in the cortical stroma, which, in turn, assures proper levels and dynamics of Ret expression in the ureteric bud tips, and thus normal ramification of the ureteric tree. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Late ascended testes: is non-orthotopic gubernacular insertion a confirmation of an alternative embryological etiology?

INTRODUCTION: Re-ascended testes account for a proportion of all undescended testes (UDTs); one main hypothesis relating to their etiology relates to a patent processus vaginalis peritonei. The aim was to investigate gubernacular insertion points in boys with late ascended testis as a possible guide to an alternative embryological etiology. PATIENTS AND METHODS: Patients with proven ascended testes were recruited from four different pediatric urology centers between May 2016 and September 2017. All patients were evaluated regarding their gubernacular insertion during orchidopexy. The presence of accompanying patent processus vaginalis and the association between the epididymis and testis were also documented. RESULTS: Seventy-seven children (mean age = 73.1 ± 41.2 months [range 18-176]) were enrolled into the study. A non-orthotopic gubernacular insertion point was found in 96.1% (n = 74); 34.2% (n = 26) of these were located in the groin and 63.2% (n = 48), high within the scrotum. Figure A. An open processus vaginalis peritonei was found in 35.1%. Twelve patients (15.6%) had small, dysplastic appearing testis with testis-epididymis dissociation. Boys with a higher insertion of the non-orthotopic gubernaculum (n = 48, groin) were operated earlier (mean age at surgery, 62.3 months) compared with those with a gubernacular insertion at a high scrotal site (mean age at surgery, 90.5 months; p = 0.004). Figure B. DISCUSSION: This study revealed that non-orthotopic gubernacular insertion is found in the vast majority of the ascending testis cases. Patent processus vaginalis was accompanying only 35.1% of all children and might be the cause of the ascending testis in this small subgroup of patients in line with the earlier reports [1]. In boys with ascending testes, in this population, the gubernaculum was very likely to insert non-orthotopically. In concordance with previous reports [2] and regarding the finding of a an earlier age at surgery in boys with higher inserting gubernacula, this could provide a logical explanation as to how these testes are initially palpable in the scrotum and then, during body growth are retracted to the groin. CONCLUSION: In 96.1% of the patients, a non-orthotopic gubernacular insertion was found. This points to embryologic etiology, complying well with earlier reports and further underlining the critical importance of timely diagnosis and treatment for this group of patients.

Cryptorchidism after the Fukushima Daiichi Nuclear Power Plant accident:causation or coincidence?

Cryptorchidism (undescended testes) is among the most common congenital diseases in male children. Although many factors have been linked to the incidence of cryptorchidism, and testicular androgen plays a key role in its pathogenesis, the cause remains unknown in most cases. Recently, a Japanese group published a speculative paper entitled, "Nationwide increase in cryptorchidism after the Fukushima nuclear accident." Although the authors implicated radionuclides emitted from the Fukushima accident as contributing to an increased incidence of cryptorchidism, they failed to establish biological plausibility for their hypothesis, and glossed over an abundance of evidence and expert opinion to the contrary. We assessed the adequacy of their study in terms of design setting, data analysis, and its conclusion from various perspectives. Numerous factors must be considered, including genetic, environmental, maternal/fetal, and social factors associated with the reporting of cryptorchidism. Other investigators have established that the doses of external and internal radiation exposure in both Fukushima prefecture and the whole of Japan after the accident are too low to affect testicular descent during fetal periods;thus, a putative association can be theoretically and empirically rejected. Alternative explanations exist for the reported estimates of increased cryptorchidism surgeries in the years following Japan's 2011 earthquake, tsunami, and nuclear crisis. Data from independent sources cast doubt on the extent to which cryptorchidism increased, if at all. In any case, evidence that radionuclides from the Fukushima Daiichi Nuclear Power Plant could cause cryptorchidism is lacking.

Función gonadal en niños y adolescentes nacidos con restricción del crecimiento intrauterino / Gonadal function in children and adolescents born with restriction of intrauterine growth

Los niños con restricción del crecimiento intrauterino (RCIU) presentan en la vida posnatal una serie de alteraciones metabólicas y hormonales, y tienen predisposición al desarrollo de obesidad, hipertensión arterial, enfermedad cardiovascular, resistencia a la insulina y diabetes tipo 2. La exposición a un ambiente intrauterino desfavorable en fases críticas del desarrollo puede tener un efecto deletéreo sobre la gónada en formación. Se realizó una revisión bibliográfica y puesta al día sobre la posible asociación entre RCIU y alteraciones de la función gonadal en niños y adolescentes de ambos sexos. Para facilitar la actualización, se dividió por etapas en: 1, prenatal; 2, posnatal y prepuberal; 3, puberal, y 4, adulta. La mayoría de los niños que nacen muy prematuros o con muy bajo peso al nacer hacen una transición sin obstáculos desde la infancia a la edad adulta con respecto a la salud reproductiva. Sin embargo, en los varones se puede observar criptorquidia, hipospadias, cáncer testicular y menor fertilidad, y en las niñas, pubertad y menarca temprana, hiperandrogenismo y síndrome de ovario poliquístico. Existen datos controvertidos y se necesitan más estudios para aclarar la relación entre el RCIU y la función hipotálamo-hipófiso-gonadal.

Low birth weight due to intrauterine growth restriction (IUGR) is associated with an increased risk of obesity, hypertension, cardiovascular disease, insulin resistance, and type 2 diabetes during postnatal life. Exposure to an unfavourable intrauterine environment in critical phases of development may have a deleterious effect on the forming gonad. The objective was to carry out a bibliographic review and update on the possible association between IUGR and alterations of gonadal function in children and adolescents of both sexes. To facilitate the update, this was divided into stages: 1, prenatal; 2, postnatal and pre-pubertal; 3, puberal, and 4, adult. Most children born preterm or with low birth weight make a normal transition from childhood to adulthood with respect to reproductive health. However, cryptorchidism, hypospadias, testicular cancer and lower fertility could be observed in boys, and early puberty and menarche, hyperandrogenism and polycystic ovarian syndrome in girls. However, the data are controversial, and further studies are needed to clarify the relationship between IUGR and pituitary gonadal function.

Undescended testis: What paediatricians need to know.

Undescended testis (UDT) occurs when something goes wrong with testicular descent from high in the abdominal cavity to the scrotum. Normal descent occurs in two steps, with the transabdominal phase controlled by a new testicular hormone, insulin-like hormone 3, and the inguinoscrotal phase controlled by androgens. The latter phase requires a complex process of migration from the inguinal abdominal wall to the scrotum and is commonly defective, leading to the high incidence (2-4%) of UDT at birth. The clinical examination of babies and infants aims to confirm the persistence of congenital UDT by 3-6 months, so surgery can be optimally timed at 6-12 months. For those boys who develop acquired UDT later in childhood, the 'ascending' testis often needs surgery between 5 years and 10 years, so all boys should be screened again for UDT at school entry.

Risk factors for cryptorchidism.

Undescended testis - known as cryptorchidism - is one of the most common congenital abnormalities observed in boys, and is one of the few known risk factors for testicular cancer. The key factors that contribute to the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases in fetal development - between 8-15 weeks (the first phase of decent) and 25-35 weeks gestation (the second phase of descent); the failure of a testis to descend permanently is probably caused by disruptions to one or both of these phases, but the causes and mechanisms of such disruptions are still unclear. A broad range of putative risk factors have been evaluated in relation to the development of cryptorchidism but their plausibility is still in question. Consistent evidence of an association with cryptorchidism exists for only a few factors, and in those cases in which evidence seems unequivocal the factor is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor could vary considerably between mother-son pairs depending on an array of genetic, maternal, placental and fetal factors - all of which could vary between regions. Thus, the role of causative factors in aetiology of cryptorchidism requires further research.

Do retractile testes have anatomical anomalies?

OBJECTIVES: To assess the incidence of anatomical anomalies in patients with retractile testis. MATERIALS AND METHODS: We studied prospectively 20 patients (28 testes) with truly retractile testis and compared them with 25 human fetuses (50 testes) with testis in scrotal position. We analyzed the relations among the testis, epididymis and patency of the processus vaginalis (PV). To analyze the relations between the testis and epididymis, we used a previous classification according to epididymis attachment to the testis and the presence of epididymis atresia. To analyze the structure of the PV, we considered two situations: obliteration of the PV and patency of the PV. We used the Chi-square test for contingency analysis of the populations under study (p<0.05). RESULTS: The fetuses ranged in age from 26 to 35 weeks post-conception (WPC) and the 20 patients with retractile testis ranged in ages from 1 to 12 years (average of 5.8). Of the 50 fetal testes, we observed complete patency of the PV in 2 cases (4%) and epididymal anomalies (EAs) in 1 testis (2%). Of the 28 retractile testes, we observed patency of the PV in 6 cases (21.4%) and EA in 4 (14.28%). When we compared the incidence of EAs and PV patency we observed a significantly higher prevalence of these anomalies in retractile testes (p=0.0116). CONCLUSIONS: Retractile testis is not a normal variant with a significant risk of patent processos vaginalis and epididymal anomalies.

Do retractile testes have anatomical anomalies?

ABSTRACT Objectives: To assess the incidence of anatomical anomalies in patients with retractile testis. Materials and Methods: We studied prospectively 20 patients (28 testes) with truly retractile testis and compared them with 25 human fetuses (50 testes) with testis in scrotal position. We analyzed the relations among the testis, epididymis and patency of the processus vaginalis (PV). To analyze the relations between the testis and epididymis, we used a previous classification according to epididymis attachment to the testis and the presence of epididymis atresia. To analyze the structure of the PV, we considered two situations: obliteration of the PV and patency of the PV. We used the Chi-square test for contingency analysis of the populations under study (p <0.05). Results: The fetuses ranged in age from 26 to 35 weeks post-conception (WPC) and the 20 patients with retractile testis ranged in ages from 1 to 12 years (average of 5.8). Of the 50 fetal testes, we observed complete patency of the PV in 2 cases (4%) and epididymal anomalies (EAs) in 1 testis (2%). Of the 28 retractile testes, we observed patency of the PV in 6 cases (21.4%) and EA in 4 (14.28%). When we compared the incidence of EAs and PV patency we observed a significantly higher prevalence of these anomalies in retractile testes (p=0.0116). Conclusions: Retractile testis is not a normal variant with a significant risk of patent processus vaginalis and epididymal anomalies.

Is there a trans-abdominal testicular descent during the second gestational trimester? Study in human fetuses between 13 and 23 weeks post conception.

OBJECTIVES: To confirm if a real inner descend of testis occurs, correlating the testicular position with fetal parameters and analyzing the position of the testes relative to the internal ring. MATERIAL AND METHODS: Twenty nine human fetuses between 13 and 23 weeks post conception (WPC) were studied. The fetuses were carefully dissected with the aid of a stereoscopic lens with 16/25X magnification and testicular position observed. With the aid of a digital pachymeter the distance between the lower pole of the kidney and the upper extremity of the testis (DK-T) was measured to show the position of the testis. During the dissection we also indicated the position of the testes relative to the internal ring. Means were statistically compared using simple linear regression and the paired T-test. RESULTS: The 58 testes had abdominal position. The DK-T in the right side measured between 0.17 and 1.82cm (mean=0.79cm) and in the left side it was between 0.12 and 1.84cm (mean=0.87cm), without statistically differences (p=0.0557). The linear regression analysis indicated that DK-T in both sides correlated significantly and positively with fetal age. All fetuses with more than 20 WPC, heavier than 350g and with CRL over 22cm had a greater distance than the average DK-T. We xobserved that the 58 testis remains adjacent to the internal ring throughout the period studied. CONCLUSIONS: The testes remains adjacent to the internal ring throughout the period studied, indicating that there is no real trans-abdominal testicular descent during the second gestational trimester.

Is there a trans-abdominal testicular descent during the second gestational trimester? Study in human fetuses between 13 and 23 weeks post conception

ABSTRACT Objectives To confirm if a real inner descend of testis occurs, correlating the testicular position with fetal parameters and analyzing the position of the testes relative to the internal ring. Material and Methods Twenty nine human fetuses between 13 and 23 weeks post conception (WPC) were studied. The fetuses were carefully dissected with the aid of a stereoscopic lens with 16/25X magnification and testicular position observed. With the aid of a digital pachymeter the distance between the lower pole of the kidney and the upper extremity of the testis (DK-T) was measured to show the position of the testis. During the dissection we also indicated the position of the testes relative to the internal ring. Means were statistically compared using simple linear regression and the paired T-test. Results The 58 testes had abdominal position. The DK-T in the right side measured between 0.17 and 1.82cm (mean=0.79cm) and in the left side it was between 0.12 and 1.84cm (mean=0.87cm), without statistically differences (p=0.0557). The linear regression analysis indicated that DK-T in both sides correlated significantly and positively with fetal age. All fetuses with more than 20 WPC, heavier than 350g and with CRL over 22cm had a greater distance than the average DK-T. We xobserved that the 58 testis remains adjacent to the internal ring throughout the period studied. Conclusions The testes remains adjacent to the internal ring throughout the period studied, indicating that there is no real trans-abdominal testicular descent during the second gestational trimester.

Cell interactions and genetic regulation that contribute to testicular Leydig cell development and differentiation.

Leydig cells, located within the interstitial compartment of the testis, are major contributors of androgen synthesis and secretion, which play an important role in testis development, normal masculinization, maintenance of spermatogenesis, and general male fertility. Accordingly, dysfunction of Leydig cells may lead to various male reproductive maladies, including primary hypogonadism, cryptorchidism, and hypospadias. A better understanding of how cell interactions and gene regulation contribute to testicular Leydig cell development and differentiation may therefore help limit the incidence of such male reproductive pathologies. Several hormones and signaling molecules have been identified as important regulators of Leydig cell differentiation and function. Recent work on the regulation of testis development, especially of Leydig cells, has focused on the Desert hedgehog and platelet-derived growth factor signaling pathways. This review outlines recent findings regarding cell interactions and gene regulation involved in the development and regulation of fetal and adult Leydig cell populations. Mol. Reprod. Dev. 83: 470-487, 2016. © 2016 Wiley Periodicals, Inc.

Male infants with hypospadias and/or cryptorchidism show a lower 2D/4D digit ratio than normal boys.

BACKGROUND: In humans the ratio of the index finger to the ring finger is sexually dimorphic, with the mean ratio being larger in women than in men. It has been suggested that this difference is related to prenatal androgen exposure. This has been further demonstrated in children with congenital adrenal hyperplasia. Normal development of the male external genitalia is linked to androgen-mediated events during gestation. We therefore wanted to determine if the 2D:4D digit ratio was normal in boys with cryptorchidism or hypospadias. METHODS: We prospectively enrolled all prepubertal patients seen in the outpatient clinic for cryptorchidism or hypospadias between September and December 2012. We then compared their 2D:4D digit ratio with two control groups made up of normal boys and normal girls. Interobserver and intraobserver variability was evaluated. RESULTS: We included 57 boys with hypospadias and/or cryptorchidism, 79 boys without genital abnormalities and 25 girls without genital abnormalities. The mean 2D:4D ratio for both hands was significantly different between the three groups, with the digit ratio for boys with genital anomalies being lower than for normal boys and normal girls (p<0.0001). CONCLUSIONS: It appears that boys with genital abnormalities (cryptorchidism and/or hypospadias) have a lower 2D:4D digit ratio than boys without genital anomalies.

Structural study of gubernaculum testis in fetuses with prune belly syndrome.

PURPOSE: We compared and contrasted the structure of the gubernaculum testis in fetuses with prune belly syndrome and normal controls. MATERIALS AND METHODS: We studied a total of 6 gubernacula from 3 male fetuses with prune belly syndrome and a total of 14 from 7 male fetuses without an anomaly. Gubernacular specimens were cut into 5 µm sections and stained with Masson trichrome to quantify connective tissue and smooth muscle cells, with Weigert stain to observe elastic fibers and with picrosirius red with polarization to observe collagen. Immunohistochemical analysis was done with tubulin to observe the nerves. Images were captured with a BX51 microscope and DP70 camera (Olympus®). Stereological analysis was done with Image-Pro and ImageJ (MediaCybernetics®) using a grid to determine volumetric density. Means were statistically compared with the Mann-Whitney test. All tests were 2-sided with p <0.05 considered statistically significant. RESULTS: Prune belly syndrome fetuses were at 17 to 31 weeks of gestation and control fetuses were at 12 to 35 weeks of gestation. Quantitative analysis showed no difference in the volumetric density of smooth muscle cells in prune belly syndrome vs control gubernacula (mean 15.70% vs 19%, p = 0.2321). Collagen fiber analysis revealed a predominance of green areas in prune belly syndrome gubernacula, suggesting collagen type III, and a predominance of red areas in control gubernacula, suggesting collagen type I. Elastic fibers were significantly smaller in prune belly syndrome gubernacula than in control gubernacula (mean 14.06% vs 24.6%, p = 0.0190). Quantitative analysis demonstrated no difference in the volumetric density of nerves in prune belly syndrome or control gubernacula (mean 5.200% vs 3.158%, p = 0.2302). CONCLUSIONS: The gubernaculum in fetuses with prune belly syndrome had altered concentrations of collagen and elastic fibers. These structural alterations could be one of the factors involved in cryptorchidism in prune belly syndrome.

The importance of the gubernaculum in testicular migration during the human fetal period

Objectives The objective of this review is to study the role of the gubernaculum in the testicular migration process during the human fetal period. Materials and Methods We performed a descriptive review of the literature about the role of the gubernaculum in testicular migration during the human fetal period. Results In the first phase of testicular migration, the gubernaculum enlarges to hold the testis near the groin and in the second phase the gubernaculum migrates across the pubic region to reach the scrotum. The proximal portion of the gubernaculum is attached to the testis and epididymis and the presence of multiple insertions in the distal gubernaculum is extremely rare. The presence of muscle and nerves in the human gubernaculum is very poor. The gubernaculum of patients with cryptorchidism has more fibrous tissue and less collagen and when the patients are submitted to hormonal treatment, the gubernaculum components alter significantly. Conclusions The gubernaculum presents significant structural modifications during testicular migration in human fetuses. .

Bifid scrotum and anocutaneous fistula associated with a perineal lipomatous tumor complicated by temporary bilateral cryptorchidism in utero mimicking ambiguous genitalia: 2-D/3-D fetal ultrasonography.

Ambiguous genitalia (AG) is a morphological diagnosis defined as genitalia not typical of a male or female. Findings mimicking AG, such as penoscrotal anomalies, anorectal malformations, and perineal lipomatous tumors, may prevent accurate identification of the fetal sex. We report a case of bifid scrotum and anocutaneous fistula associated with a perineal lipomatous tumor complicated by temporary bilateral cryptorchidism in utero, which were findings mimicking AG. Several perineal anomalies are associated developmental occurrences. In the present case, the combination of bifid scrotum and temporary bilateral cryptorchidism in the male fetus mimicked the combination of clitoromegaly and prominent labia, which are commonly observed in female fetuses. However, serial systemic assessments using prenatal 2-D/3-D ultrasonography and magnetic resonance imaging were unable to detect the anocutaneous fistula and differentiate the perineal lipomatous tumor. This case report suggests that the prenatal detection of perineal abnormalities may warn obstetricians of potentially undetected congenital perineal anomalies.

Testicular migration chronology: do the right and the left testes migrate at the same time? Analysis of 164 human fetuses.

OBJECTIVE: To determine if the right and the left testes migrate at the same time during the human fetal period. SUBJECTS AND METHODS: We studied 164 human fetuses (328 testes) ranging in age from 12 to 35 weeks post-conception. The fetuses were carefully dissected with the aid of a stereoscopic lens at ×16/25. The abdomen and pelvis were opened to identify and expose the urogenital organs. Testicular position was classified as: (a) Abdominal, when the testis was proximal to the internal ring; (b) Inguinal, when it was found between the internal and external inguinal rings); and (c) Scrotal, when it was inside the scrotum. RESULTS: The testes were abdominal in 71% of the cases, inguinal in 9.41%, and scrotal in 19.81%. There was asymmetry in testicular migration in nine cases (5.5%). In three of these nine cases, one testis was situated in the abdomen and the other in the inguinal canal; in another three one testis was situated in the abdomen and the other in the scrotum, and in the remaining three, one testis was in the inguinal canal and the other in the scrotum. In five of the nine cases of asymmetry, the right testis completed the migration first, but this was not statistically significant. CONCLUSION: Asymmetry in testicular migration is a rare event, accounting for <6% of the cases. The right testis seems to complete migration first.

The importance of the gubernaculum in testicular migration during the human fetal period.

OBJECTIVES: The objective of this review is to study the role of the gubernaculum in the testicular migration process during the human fetal period. MATERIALS AND METHODS: We performed a descriptive review of the literature about the role of the gubernaculum in testicular migration during the human fetal period. RESULTS: In the first phase of testicular migration, the gubernaculum enlarges to hold the testis near the groin and in the second phase the gubernaculum migrates across the pubic region to reach the scrotum. The proximal portion of the gubernaculum is attached to the testis and epididymis and the presence of multiple insertions in the distal gubernaculum is extremely rare. The presence of muscle and nerves in the human gubernaculum is very poor. The gubernaculum of patients with cryptorchidism has more fibrous tissue and less collagen and when the patients are submitted to hormonal treatment, the gubernaculum components alter significantly. CONCLUSIONS: The gubernaculum presents significant structural modifications during testicular migration in human fetuses.

Journal of Pediatric Surgery-Sponsored Fred McLoed Lecture. Undescended testis: the underlying mechanisms and the effects on germ cells that cause infertility and cancer.

Testicular descent is a complex morphological process that occurs in at least 2 stages, with different hormonal control. Insl3 controls the first step of gubernacular enlargement, although the abnormality long gubernacular cord in persistent Mullerian duct syndrome remains unexplained. Androgens control inguinoscrotal migration, which may be triggered by local signalling from the mammary line, and which requires the genitofemoral nerve. However, there is still much to learn about this phase, which when abnormal frequently leads to cryptorchidism. Orchidopexy is being recommended in the first year of age, because increasing research suggests that the stem cells for spermatogenesis form between 3 and 9 months, with surgery aiming to permit this normally, although this is not yet proven. Acquired cryptorchidism is now becoming accepted and is likely to be caused by inadequate elongation of the postnatal spermatic cord. It is not yet known whether orchidopexy is always needed, as this remains controversial.