Are there anatomical limiting factors to foreskin reconstruction at the time of single-stage hypospadias repair?

INTRODUCTION: Foreskin reconstruction (FR) at the time of primary hypospadias repair is a truly anatomically complete reconstruction of the hypospadic penis. We prospectively collected penile and preputial measurement of children undergoing single-stage hypospadias repair and FR with the aim to identify possible relations between penile and preputial anatomy and the likelihood to develop complications. MATERIALS AND METHODS: We prospectively studied children who underwent single stage hypospadias repair associated with FR from 2016 to 2019. We recorded intra-operative foreskin and penile measurements and post-operative outcomes. Logistic Regression analysis was performed to explore independent factors affecting urethroplasty and skin complications. Chi square test was used to compare outcomes in different groups based on ventral foreskin defect (VFD) width, Glans size, age at surgery and meatal location. RESULTS: From a total of 181 consecutive patients, 86 boys who underwent a single stage hypospadias repair combined with FR were included in the study. Patients were excluded because they were either lost at follow up (n = 10), required a 2-stage repair (n = 2), were circumcised at birth (n = 3) or parents requested a circumcision (n = 78); in 2 patients, a decision to perform circumcision was made intraoperatively due to aesthetic reasons (monk-hood deformity of the prepuce). Median age at surgery was 17 months. Mean glans width was 14.4 mm. Mean unstretched and stretched foreskin circumference were 29.5 mm and 40.9 mm, respectively. Mean VFD (the distance between the proximal insertion of the foreskin hood on either side of the midline at the level of the coronal sulcus) was 7.2 mm (Fig. 1). At median follow-up of 8 months (6-23), 9 complications were recorded (10.4%): foreskin dehiscence occurred in 1% (1/86), a foreskin fistula was noted in 4.6% (4/86), tight, non-retractile, foreskin in 1% (1/86); urethrocutaneous fistula in 2.3% (2/86) and complete dehiscence of the glans and foreskin in 1 (1.2%). Multiple logistic regression analysis demonstrated that none of the measurements obtained was an independent risk factor for developing urethroplasty or skin complications. There was no significant difference in complications between wide VFD (>7 mm) vs. narrow VFD (≤7 mm), large glans (>14 mm) vs. small glans (≤14 mm), age at surgery ≤24 months vs. > 24 month and meatal location distal (glanular, coronal, subcoronal and distal penile) vs. proximal (midpenile, proximal penile and penoscrotal). CONCLUSION: To the best of our knowledge, this is the first study reporting a prospective and objective assessment of the foreskin in the context of single stage hypospadias repair. Individual anatomical differences in preputial and penile anatomy do not seem to affect the likelihood of skin and urethroplasty complications. FR can, therefore, be offered to all boys undergoing primary single stage hypospadias repair . Further studies on larger numbers and external validation of these measurements is necessary.

Double versus single diaper technique after hypospadias repair, does it really matter?

INTRODUCTION: Double-diaper technique with an open-drainage catheter is a common practice after hypospadias repair. However, double-diapering may increase the burden of postoperative care and has not been compared to single-diapering with an open-drainage catheter. OBJECTIVES: This study investigates whether the single-diaper technique is associated with inferior surgical outcomes compared to the double-diaper technique. MATERIALS AND METHODS: A single surgeon database was retrospectively reviewed for patients who underwent hypospadias repair between 2013 and 2021. Patients who were lost to follow-up and those in whom the type of diaper care (single- or double-diaper) was not documented were excluded. Patients in the single-diaper technique received the same type of dressing and discharge instructions, as those in the double-diaper group, except for leaving the catheter freely draining into a single-diaper. Short-term complications including surgical site infection (SSI), urinary tract infection (UTI) and wound dehiscence, were the primary outcome; whereas the long-term urethroplasty complications (urethrocutaneous fistula and meatal stenosis) were secondary outcomes. Outcomes were analyzed according to the type of diaper care. RESULTS: Among 323 patients reviewed, 219 patients met the inclusion criteria (72 patients in the double-diaper and 147 in the single-diaper group). Both study groups were similar regarding patient demographics, hypospadias characteristics and surgical technique. Looking at the primary outcomes, there was no statistically significant difference in SSI, UTI or wound dehiscence. For the secondary outcomes, the incidence of meatal stenosis (8.3 vs. 1.4%, p = 0.044), and fistula formation (15.3% vs 5.4%, p = 0.037) was significantly higher in the double-diaper than the single-diaper group, respectively (Table 2). CONCLUSION: Single-diaper technique following hypospadias repair is not associated with increased risk of complications compared to double-diaper technique.

Urethral advancement and glanuloplasty versus tubularized incised plate urethroplasty for distal hypospadias repair: a prospective randomized study.

BACKGROUND: About one in 200 to one in 300 male births has hypospadias. The prevalence of this congenital anomaly varies worldwide. The meatus is located distally in approximately 70% of cases. Several surgical techniques were described for distal hypospadias repair; despite this, there is no ideal approach. This study compares urethral advancement &glanuloplasty, and TIP techniques in terms of feasibility, duration of operation, and complications. Patients and. METHODS: This prospective randomized comparative study was conducted at Al-Azhar University Hospitals from April 2022 to October 2022. Fifty-seven cases with different types of hypospadias were assessed for eligibility. Among them, seven cases were excluded due to the presence of severe chordee (n = 3), proximal variant (n = 2), and recurrent cases of hypospadias (n = 2). Fifty cases were randomly divided into two groups using a 1:1 ratio (computer-generated randomization). Twenty-five cases were subjected to urethral advancement and glanuloplasty, and the rest were subjected to tubularized incised plate (TIP) urethroplasty. RESULTS: The mean age of all studied cases was 4.2 years. Approximately 52% had coronal or sub-coronal meatus, whereas 48% had glandular meatus. Both groups were matched according to age and meatus location (p > 0.05). No statistically significant difference was observed between the two groups regarding duration of operation, postoperative pain, and postoperative hospital stay. In addition, both groups did not differ significantly in late complications (meatal stenosis, meatal retraction, fistula, and glans dehiscence). CONCLUSIONS: Both urethral advancement &glanuloplasty, and TIP urethroplasty have comparable short-term outcomes. Urethral advancement and glanuloplasty is preferred in certain conditions, especially in circumcised children or those with a narrow urethral plate. TRIAL REGISTRATION: The study protocol was approved by the Pan African Clinical Trials Registry (number for the registry is: PACTR202211757905870) on (29/11/2022). All procedures were performed per the Helsinki Declaration.

Caudal anesthesia is not associated with post-operative complications following distal hypospadias repair.

INTRODUCTION: The use of caudal anesthesia at the time of hypospadias repair remains controversial as some prior studies have reported increased postoperative complication rates associated with caudal nerve block. However, these results have been called into question due to confounding factors and heterogeneous study groups. OBJECTIVE: Given the importance of identifying true risk factors associated with increased hypospadias complication rate, we examined our experience with caudal anesthesia limiting our analysis to distal repairs. We hypothesized that caudal anesthesia would not be associated with increased postoperative complications. STUDY DESIGN: We retrospectively reviewed our institutional hypospadias database from June 2007 to January 2021. All boys who underwent single-stage distal hypospadias repair with either caudal or penile block with minimum 1 month follow up were included. Records were reviewed to determine the type of local anesthesia, type of hypospadias repair, all complications, and time to complication. Association between any complication and local anesthesia type was evaluated by univariate and multivariate logistic regression analysis controlling for age at surgery and type of repair. A sub-analysis was performed for complications occurring ≤30 days. RESULTS: Overall, 1008 boys, 832 (82.5%) who received caudal and 176 (17.5%) penile block, were included. Median age at surgery was 8.1 months and median follow up was 13 months. Overall complication rate was 16.4% with 13.8% of patients requiring repeat operation. Median time to complication was 10.59 months and was significantly shorter in the caudal group (8.45 vs. 25.2 months). Caudal anesthesia was associated with higher likelihood of complication on univariate analysis; however, this was not true on multivariate analysis when controlling for age and type of repair. Caudal anesthesia was not associated with increased likelihood of complication within 30 days. DISCUSSION: Since the association between caudal anesthesia and hypospadias complications was first suggested, several studies have tried to answer this question with variable results. Our findings add to the evidence that there is no association between caudal anesthesia and increased hypospadias complications in either the short or long term. The major strengths of our study are a large, homogenous study population, robust follow up and inclusion of data from 14 surgeons over 14 years. Limitations include the study's retrospective nature as well as lack of standardized follow up protocol throughout the study period. CONCLUSIONS: After controlling for possible confounders, caudal nerve block was not associated with increased risk of postoperative complications following distal hypospadias repair.

Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models.

BACKGROUND: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. SUMMARY: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. KEY MESSAGES: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Hipospadias: del diagnóstico ecográfico prenatal al manejo posnatal / Hypospadias: from prenatal ultrasound diagnosis to postnatal management

El hipospadias es la localización anormal del meato urinario y es la malformación de genitales externos más frecuentemente diagnosticada. El diagnóstico prenatal es posible mediante ecografía sistemática desde la semana 20 de gestación, siendo más fácil su diagnóstico en el tercer trimestre. Las formas leves suelen ser aisladas, familiares o asociadas a disfunción placentaria o restricción de crecimiento intrauterino, mientras que las formas más graves presentan hasta un 30% de asociación a defectos fetales, anomalías cromosómicas/genéticas o anomalías del desarrollo sexual. La tríada para el diagnóstico ecográfico prenatal consiste en curvatura ventral del pene, anomalía del prepucio dorsal y punta del pene roma. La valoración de la uretra durante la micción y el aspecto del chorro miccional son de gran utilidad para clasificar el defecto. Cuando se diagnostica hipospadias peneano o escrotal es aconsejable realizar una amniocentesis para estudio genético fetal y valorar otros signos de adecuada virilización, como el descenso testicular a partir de la semana 27. El seguimiento tras el parto debe ser multidisciplinario, incluyendo urólogo y endocrinólogo infantil. En hipospadias leves el pronóstico es bueno con reparación quirúrgica en el primer año de vida, pero las formas graves pueden presentar un reto mayor para su corrección funcional y estética.

Hypospadias refers to the abnormal location of the meatus; it is the most common genital malformation detected in the fetus and newborn. Prenatal diagnosis is feasible from 20 weeks onwards with routine ultrasound; however, it is easier to diagnose during the third trimester of pregnancy. Mild defects are usually isolated, familiar o related to placental disfunction or intrauterine growth restriction, while the severe hypospadias are associated to other fetal defects, genetic or chromosomal abnormalities or disorders of sex development. In about 30% of cases. The triad of ultrasound findings prenatally is ventral curvature of the penis, redundant dorsal foreskin and blunt distal penis. The identification of the urethra during the micturition and the direction of the urinary stream help in the classification of the defect. When severe hypospadias is detected, the recommendation is to perform genetic amniocentesis and search for other ultrasound findings related to poor virilization in the fetus, as testicular descent after 27 weeks of gestation. Postnatal follow up should be multidisciplinary including infantile urologist and endocrinologist. The prognosis in distal hypospadias is usually good following surgical repair, however in severe cases surgical interventions may be more challenging in order to obtain satisfactory outcome in terms of function and esthetic.

A multicenter study on surgical procedure selection and risk factor analysis of postoperative complications after TIP and Duckett hypospadias repair.

BACKGROUND: Hypospadias is a common congenital malformation in pediatric urology with surgery being the only curative treatment. Although there are hundreds of surgical methods for hypospadias, no single method can treat all types, and there are still high rates of postoperative complications. We performed this study to investigate surgical procedure selection and perform risk factor analysis of postoperative complications in hypospadias repair. METHODS: Retrospective analysis was performed of complete clinical and follow-up data of children with hypospadias who were treated and followed up at 15 children's clinical centers in Mainland China from December 2018 to December 2019. Children were divided into groups according to Barcat classification and surgical methods in order to analyze the surgical choice for different types of hypospadias and the influencing factors of different surgical methods for complications. RESULTS: In total, 1011 patients were followed up for 26 months. According to Barcat classification, there were 248 cases of distal type hypospadias, 214 of intermediate, and 549 of proximal type. Transverse preputial island flap urethroplasty (Duckett) and tubularized incised plate urethroplasty (TIP) were performed in 375 (37.1%) and 336 cases (33.2%), respectively. The postoperative complication rate of distal hypospadias was 23.4% (15.8-57.1%), mid shaft 29.0% (22.7-40.0%), and proximal 43.7% (30.2-52.9%). Among the 375 patients in Duckett group, 192 had complications. Multivariate logistic analysis showed that the length of prepuce island flap (OR = 3.506, 95% CI: 2.258-5.442) was an independent risk factor for complications after Duckett operation (P < 0.001). In TIP group, there were 336 cases with 84 complications. Multivariate logistic analysis showed that the width of urethral plate after longitudinal resection (OR = 0.836, 95% CI: 0.742-0.942) and glans width (OR = 0.851, 95% CI: 0.749-0.965) were independent risk factors for postoperative complications after TIP (P = 0.003, P = 0.012). CONCLUSION: Several anatomical features play a role during the selection process among the different surgical approaches, including glans size, urethral plate width, and the meatal position. The width of the urethral plate and glans width were risk factors for postoperative complications after TIP. The length of prepuce island flap was a risk factor for complications after Duckett operation.

Analysis in the influence factors of urethroplasty in DSD.

BACKGROUND: At present, there is no specific research on the factors affecting the success rate of urethroplasty in patients with DSD. The purpose of this study is to explore the factors affecting the success of urethroplasty in DSD patients, and to provide some reference for the surgical treatment of DSD patients undergoing urethroplasty. METHOD: We reviewed patients with DSD who underwent urethroplasty from January 2016 to December 2019 retrospectively. Patients were divided into four groups: the successful group, the urethrocutaneous fistula group, the urethral diverticulum group, and the urethral stricture group. Risk factors were determined from the following data included the DSD classification, the age of first operation, length of urethral defect, degree of hypospadias, cryptorchidism, micropenis, gonad type, hormone therapy before operation, transposition of penis and scrotum, surgical strategy, urethral covering material, and postoperative catheter removal time. We explored the difference of each factor between four groups through the comparative study of single factor and multifactor logistic regression analysis of related factors. RESULT: 122 cases were enrolled in this group (n = 122), 12 cases were lost to follow-up. Median follow-up was 28 months (12-55 months).We found the success rate of operation decreased with longer urethral defect (B = - 0.473, P = 0.005). The success rate of operation was higher in staged operation and TPIT (TPIT = Transverse Preputial Island Tube operation)-related operation than primary operation (B = 1.238, P = 0.006) and TPIT-nonrelated operation (B = 2.293, P = 0.001). Although there was a significant difference between the age of the first operation and the occurrence of urethrocutaneous fistula (P = 0.006 < 0.05), there was no significant difference in logistic regression analysis (P = 0.161 > 0.05). The incidence of urethrocutaneous fistula was lower in TPIT-related operation than in TPIT-nonrelated operation (B = - 2.507, P = 0.000). The incidence of postoperative urethral diverticulum was lower in staged operation than in primary operation (B = - 1.737, P = 0.015). CONCLUSION: For patients with disorder of sex development undergoing urethroplasty, the length of urethral defect is an independent risk factor affecting both the success rate of operation and the urethrocutaneous fistula. The age of the first operation has a statistically significant effect on the occurrence of postoperative urethrocutaneous fistula, but it is not an independent factor. Urethrocutaneous fistula is less found in TPIT-related operation in the study. Staged operation is an independent protective factor for postoperative urethral diverticulum compared with one-stage operation but isn't related to urethrocutaneous fistula.

A new modified Duckett urethroplasty for repair of proximal hypospadias with severe chordee: outcomes of 133 patients.

BACKGROUND: Despite the continuous development and evolution of surgical methods and techniques, proximal hypospadias remains one of the most challenging issues for pediatric urologists. This study aims to evaluate the indications and postoperative complications of our new modified Duckett urethroplasty. METHODS: A total of 133 patients with proximal hypospadias who underwent repair of the modified Duckett urethroplasty from February 2016 to February 2021 were reviewed. The median age of patients was 3 years (range 1-16). All patients had severe chordee. One senior experienced pediatric urologist performed all the surgeries. Catheter was removed 14 days after the surgery. RESULTS: The location of the urethral meatus was proximal penile in 26 patients (19.5%), penoscrotal in 60 (45.1%), scrotal in 31 (23.3%), and perineal in 16 (12.0%). The mean length of the urethral defect was 4.5 cm (range 2.5-10). The median duration of follow-up was 46 months (range 8-67). Complications occurred in 31 patients (23.3%), including urethra-cutaneous fistula in 22 (16.5%), urethral stenosis in 7 (5.3%), and urethral diverticulum in 2 (1.5%). No recurrent chordee were found in all cases. All patients who developed complications were treated successfully at our hospital. CONCLUSIONS: Our modified Duckett urethroplasty showed functionally and cosmetically favorable outcomes, with a lower incidence of postoperative complications. To the best of our knowledge, the novel Duckett technique is a feasible and suitable option for patients who suffer from proximal hypospadias with severe chordee and dysplasia of the urethral plate.

Urethral complex thickness and thickness index are the independent risk factors for urethroplasty complications after tubularized incised plate hypospadias repair.

INTRODUCTION: In tubularized incised plate urethroplasty, the depth of the mid-line relaxing incision is the key factor for urethral plate tubularization without tension. The incision depths will be different from one case to the other even if they have been done by the same surgeon. This difference in depths resulted from the different thicknesses of the urethral plate and the underlying corpus spongiosum (urethral complex). OBJECTIVES: To evaluate the urethral complex thickness and thickness index as risk factors for the complications of TIPU in penile shaft hypospadias repair. STUDY DESIGN: All primary penile shaft (distal and mid-penile) hypospadias (with or without mild penile chordee) were operated with TIPU between March 2018 and February 2021. We measured the urethral complex thickness in the hypospadiac and proximal normal parts of urethra pre-operatively with superficial U/S probe. Intraoperative, we measured the urethral plate width before and after the midline relaxing incision, calculate the relative increase in urethral plate width (RIUPW). Stepwise logistic regression assessed the effect of different variables on the complication rate. These variables include; urethral plate width before and after incision, urethral complex thickness, thickness index, RIUPW, site of hypospadiac meatus and patients ages. RESULTS: 10 cases had 11 complications (12.7%). Fistulae were the commonest complication (8.9%). Complication rate has significant negative correlations with many variables on Univariate analysis. Stepwise logistic regression shows that urethral plate thickness and thickness index are the independent risk factors for complications after TIPU in penile shaft hypospadias. DISCUSSION: Urethral plate width was suggested to be a risk factor for TIPU complications. In our study, Univariate analysis shows that complications were more with plate width ˂8 mm but without significant difference (P = 0.487). Also it shows that post incision width and RIUPW have significant negative correlation with complications rate. Multivariate analysis showed that the urethral complex thickness and thickness index are the independent risk factors for complications after TIPU hypospadias repair (AUC 0.94 95% CI 0.894-0.972 P Ë‚ 0.001 and 0.965 95% CI 0.921-0.996, respectively). CONCLUSION: The thickness of the urethral plate and the underlying spongiosum is the determining factor for TIPU success. We can use it as an objective reproducible assessment tool for urethral plate quality and to predict TIPU complications.

[Staged Duckett urethroplasty and Byars reconstruction for severe hypospadias with dysplastic glans].

OBJECTIVE: To study the effects of staged Duckett urethroplasty and Byars reconstruction in the treatment of severe hypospadias with dysplastic glans. METHODS: We retrospectively analyzed the clinical data on 57 cases of severe hypospadias with dysplastic glans treated by two-stage Duckett urethroplasty or Byars reconstruction from September 2015 to May 2020. At stage-Ⅰ treatment, the patients were aged from 5 to 47 (mean 21) months, the diameter of the glans less than 1.4 cm, and the interval between the two stages from 6 to 41 (mean 14) months. The patients underwent Duckett urethroplasty, distal in stage Ⅰ and proximal in stage Ⅱ (group A, n = 25) or Byars reconstruction with the urethral plate in stage Ⅰ and Duplay urethroplasty in stage Ⅱ (group B, n = 32). Postoperative follow-up lasted 12－56 (mean 35) months. RESULTS: After stage Ⅱ surgery, penile straightening and smooth appearance of the graft were achieved in all the patients. Six cases of postoperative complications (24%) were observed in group A, including 4 cases of urinary fistula, 1 case of glans dehiscence, 1 case of urethral diverticulum and 1 case of urethral stricture, while 14 cases (43.8%) were observed in group B, including 9 cases of urinary fistula, 9 cases of glans dehiscence and 2 cases of urethral diverticulum, with a remarkably lower incidence rate of glans dehiscence in group A than in B (P = 0.043), but no statistically significant difference in the other observations between the two groups (P > 0.05). CONCLUSION: Both staged strategies of Duckett urethroplasty and Byars reconstruction can be used for the treatment of severe hypospadias with dysplastic glans, but the latter may result in a higher incidence rate of glans dehiscence postoperatively and bring more difficulties to subsequent repair.

Hypospadias and the Use of the Ages and Stages Questionnaire to Evaluate Neurodevelopmental Status of Boys with Hypospadias.

INTRODUCTION: Placental insufficiency is one of the reasons for the reduction of hormone production. Thus, if one of the suspected causes of hypospadias is placental insufficiency, then the neurodevelopmental status of boys with hypospadias may be impaired. The aim of this study was to evaluate the neurodevelopmental status of boys with hypospadias and guide the parents of those who need support to related departments for early intervention. MATERIALS AND METHODS: Boys were divided into two groups, those with hypospadias (group H) and healthy children undergoing traditional circumcision (group C). The parents of the boys completed the Ages and Stages Questionnaire (ASQ) and ASQ-Social Emotional (SE), both of which are screening instruments for the early identification of developmental and social-emotional problems, respectively. RESULTS: Seventy-eight boys had hypospadias and 59 were admitted for traditional circumcision. The group H had statistically significant more impaired scores than group C in communication, gross motor, and personal-social skill sections. The multivariate logistic regression analysis revealed that hypospadias was the independent predictive factor for communication and personal-social skills. CONCLUSION: Hypospadias and neurologic impairment may share common etiologic factors. Accordingly, physicians should keep in mind that if a boy presents with hypospadias, the possibility of having neurologic impairment is higher than normal population and early intervention has crucial importance. Every boy with hypospadias should be evaluated for neurodevelopmental status.

Exploring the risk of hypospadias in children born from mothers living close to a vineyard.

Hypospadias (H) is a common birth defect affecting the male urinary tract. It has been suggested that exposure to endocrine disrupting chemicals might increase the risk of H by altering urethral development. However, whether H risk is increased in places heavily exposed to agricultural pesticides, such as vineyards, remains debated and difficult to ascertain. The objective of the work is to test the possible association of H with residential proximity to vineyards. Residential address at birth of 8,766 H cases born 1980-2011 was taken from 17 specialized surgery centers. The geographical distribution of vineyards was obtained from the European Land Parcel Identification System (LPIS) and the distance of address to the nearest vineyard was computed. A first estimate of the variation of H relative risk with distance to vineyards was obtained using as controls 13,105 cryptorchidism (C) cases operated during the same period in the same centers. A separate estimate was obtained from a case-control study using "virtual controls" (VC) defined as points of the map sampled to match the demographic distribution of births within the recruitment territories of the study centers. Non-exposed patients were defined as those with a residence between 5,000 and 10,000 m from the closest vineyard. The residential distance to vineyard was smaller for H than for C cases (p<10-4). We found 42/8766 H cases (0.48%) and 50/13,105 C cases (0.38%) born to mothers living within 20 m of a vineyard. The odds ratios for H were 2.48 (CI: 1.0 to 5.1) and 2.4 (CI: 1.3 to 4.4), vs C or vs VC, respectively, when pregnant mothers lived 10-20 m from a vineyard. In conclusion, our study supports that children born to mothers living close to a vineyard have a two-fold increased risk of H. For environmental research, the use of VC provides an alternative to classical case control technique.

Androgen receptor expression in preputial dartos tissue correlates with physiological androgen exposure in congenital malformations of the penis and in controls.

INTRODUCTION: The androgen receptor (AR) plays an important role in the development of male genitalia, and impaired androgen signalling has been hypothesised to underlie congenital penile malformations (CPM) such as hypospadias. Previous studies exploring the role of AR expression in the development of CPM have yielded conflicting results. OBJECTIVES: To assess AR expression in human foreskin of boys/men born with hypospadias, buried penis versus controls. STUDY DESIGN: Foreskin samples of 428 boys and men undergoing primary penile surgery (198 controls, 197 hypospadias, and 33 buried penis) were collected between October 2013 and July 2018. AR staining was performed in all samples and semi-quantitatively scored by two researchers independently, using a modified quick score (mQuicks) that assesses the proportion and intensity of AR staining in smooth muscle fibres. RESULTS: The interobserver variability of the mQuicks had a high level of agreement for the total score, as well as for the subscores. Two phases of high AR expression were observed in all groups, the first following the postnatal gonadotropin surge (i.e., mini-puberty) and the second in (pre-) puberty. No differences in AR expression were found in hypospadias or buried penis cases as compared to controls matched for age at time of surgery. DISCUSSION: This study describes the physiological evolution in AR expression in the human foreskin of boys with CPM and explains the cause of the previously reported, conflicting results. Despite the very large cohort, the limitations of this study are the low number of cases younger than six months at the time of surgery and the lack of Tanner stages to correlate with the mQuicks in adolescents. CONCLUSIONS: The mQuicks is a straightforward and informative tool to semi-quantitatively assess AR expression in the dartos tissue. In this study, AR expression in human foreskin shows a bimodal distribution in boys with CMP and controls, following physiological androgen exposure. No statistically significant difference in AR expression could be found between both groups. Whether other local mechanisms are affected by these physiological changes is currently unclear. However, strict age-matching should be considered when exploring the mechanisms underlying disturbed penile and urethral development in CMP.

Retardation of Preputial Wound Healing in Rats with Hypospadias Induced by Flutamide.

Objective: The aim of this study was to identify a theoretical support for the prevention of urethral fistula following hypospadias repair, by comparing the preputial wound healing process in Sprague-Dawley (SD) rats with and without hypospadias induced by flutamide. Methods: Fifteen pregnant SD rats were randomly divided into three groups. These rats in one group received the androgen receptor antagonist flutamide (25 mg/kg/day) from gestation days 11-17, to establish a rat model of hypospadias for further study of the molecular mechanisms of the hypospadias etiology. The pregnant rats in the control groups were not administered flutamide. The pups from the control and experiment groups underwent an incision on the dorsal prepuce on postnatal day 25 and were sacrificed on postoperative days 3, 7, and 14 to collect penis samples. The penis morphology was examined in all groups. Subsequently, transforming growth factor ß1 (TGF-ß1), α-smooth muscle actin (α-SMactin), and signal transducers and activators of the transcription 3 (STAT3) expression levels in the different groups were measured at the indicated time points postoperatively using qRT-PCR and Western blot. Results: There was less regeneration of the subcutaneous tissue in hypospadias rats than in the sham-operated group (P < 0.05) on postoperative day 3. No differences were found in the regeneration of the subcutaneous tissue between these groups on postoperative days 7 or 14. Additionally, there were no differences in the epithelial cell regeneration between the control and the hypospadias groups at any postoperative timepoint. Moreover, the expression levels of TGF-ß1, α-SMactin, and STAT3 were all significantly lower in hypospadias group than that in the sham-operated group (P < 0.05). Conclusion: The results from the present work suggest that preputial wound healing is retarded in rats with hypospadias induced by flutamide and that this retardation might result from multi-gene regulation.

[A CASE OF SPLENOGONADAL FUSION PRESENTING NON-PALPABLE TESTIS AND PROXIMAL HYPOSPADIAS].

A 9-month-old boy, having a history of cardiac surgery in neonatal period, was referred to our department for evaluation of genital anomalies. The antenatal course was uneventful, except for unknown gender. His family history was unremarkable. He was delivered at full term, and his birth weight was 3,510 g. Physical examination revealed proximal hypospadias and a non-palpable testis on the left side. Chromosome studies showed a normal male karyotype with positive SRY. At the age of 14 months, he underwent hypospadias repair. Three months later, left testicular exploration was performed along with orchidopexy of an ascending testis on the contralateral side. As nothing was found through an inguinal incision on the left side, laparoscopy was indicated. Laparoscopic observation revealed a small dark reddish mass cranially connected to the left hypoplastic testis that was located high in the left iliac fossa. The epididymis and vas deference looked abnormal, and detachment to the testis was apparent. Testicular vessels were undifferentiated from the mass. Therefore, the left testis was excised with the mass. Histopathological examination confirmed the testis and spleen tissue, and the diagnosis of splenogonadal fusion was made postoperatively.

A loss of estrogen signaling in the aromatase deficient mouse penis results in mild hypospadias.

Hypospadias is the abnormal opening of the urethra on the underside of the penis and occurs in approximately 1/125 live male births worldwide. The incidence rate of hypospadias has dramatically increased over the past few decades. This is now attributed, at least in part, to our exposure to endocrine-disrupting chemicals (EDCs) which alter the hormonal signals required for development of the penis. In humans androgens are the main drivers of fusion of the urethral folds to form the urethra within the shaft of the penis, a process required for termination of the urethra in its normal location at the tip of the penis. However, recent research has suggested that estrogen also plays a role in this process. To better understand how EDCs impact urethral development it is essential that we understand the normal function of hormones during development of the penis. To define the role of estrogen in urethral development we examined development of the penis in the aromatase (Cyp19a1) Knockout (ArKO) mouse strain in which endogenous estrogen production is completely ablated. We found that the ArKO penis had a mild hypospadias phenotype. The developing ArKO postnatal penis displayed an early disruption in preputial development, which likely causes the mild hypospadias observed in adults. Using qPCR, we found altered expression of keratin genes and key urethral patterning genes in response to the disrupted estrogen signaling. The hypospadias phenotype was almost identical to that reported for the estrogen receptor α (ERα) knockout confirming that ERα is the predominant receptor for mediating estrogen action during development of the mouse penis. Our results show that estrogen is required for normal prepucial development and placement of the mature urethral opening at the distal aspect of the penis. We also identified several genes which are potential downstream targets of estrogen during normal urethral closure. With this knowledge, we can now better understand how anti-estrogenic as well as estrogenic EDCs disrupt urethral closure to cause mild hypospadias in both mice and humans.

Occupational exposure to endocrine-disrupting chemicals and other parental risk factors in hypospadias and cryptorchidism development: a case-control study.

AIM OF THE STUDY: Endocrine-disrupting chemicals (EDCs) are exogenous agents that are capable of altering the endocrine system functions, including the regulation of developmental processes. The aim of this study was to investigate the association between EDC exposure and other parental factors in the etiology of hypospadias and cryptorchidism. METHODS: A case-control study was conducted. Cases (n = 210) were infants aged between 6 months and 14 years diagnosed with hypospadias or cryptorchidism who attended the authors' hospital over a period of 18 months, and controls (n = 210) were infants within the same range of age and without any urological disorders who attended the outpatient clinic of the same hospital during the same time period. Their selection was independent of exposures. Data on parental occupational exposure to EDCs and other sociodemographic variables were collected through face-to-face interviews and systematically for both cases and controls. Crude and adjusted odds ratios (ORs) were estimated to control for confounding with their 95% confidence interval (CI) by means of logistic regressions. Specifically, three final models of a dichotomous outcome were constructed: one for cryptorchidism, one for hypospadias, and the third considering both malformations together. The Hosmer-Lemeshow test was used to assess the goodness of fit of the models. Their discriminatory accuracy (DA) was ascertained by estimating their areas under the receiver operating characteristic curves area under the curve (AUC) along with their 95% CI. RESULTS: Associations were found between advanced maternal age (OR adjusted = 1.82; 95% CI: 1.14-2.92), mother's consumption of anti-abortives (OR = 5.40; 95% CI: 1.40-38.5) and other drugs (OR = 2.02; 95% CI: 1.31-3.16) during pregnancy, maternal and paternal occupational exposure to EDCs (OR = 4.08; 95% CI: 2.03-8.96 and OR = 3.90; 95% CI: 2.41-6.48, respectively), fathers smoking (OR = 2.0; 95% CI: 1.33-2.99), and fathers with urological disorders (OR = 2.31; 95% CI: 1.15-4.90). Maternal and paternal high educational level could be protective of cryptorchidism (OR = 0.47; 95% CI: 0.28-0.76 and OR = 0.63; 95% CI: 0.42-0.93, respectively). The DA of the models for the whole sample (AUC = 0.75; 95% CI: 0.70-0.79) for cryptorchidism (AUC = 0.76; 95% CI: 0.71-0.82) and for hypospadias (AUC = 0.75; 95% CI: 0.69-0.81) was moderately high. CONCLUSIONS: Advanced age, some parental occupational exposure to EDCs, some drug consumption, smoking, and the father's history of urological disorders may increase risk and predict the developments of these malformations. Studies with higher samples sizes are needed to assess associations between individual EDC occupational exposures and drugs and these malformations.

Long-term consequences of androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is one of the most common sexual developmental disorders. According to the grade of the remaining androgen receptor (AR) function, AIS is classified as complete (CAIS), partial (PAIS) or mild (MAIS). In CAIS, the prevalence of germ cell tumours is increased compared with the general population. Although patients with CAIS used to undergo gonadectomy before puberty, nowadays a gonadectomy is recommended after spontaneous puberty, and up to 15% of patients retain their gonads. Nevertheless, the risk of germ cell tumour increases gradually after puberty. Annual follow-up with ultrasound or magnetic resonance imaging (MRI) is recommended. Unfortunately, these imaging methods are not sensitive enough for the diagnosis of an in situ germ cell tumour. In PAIS, the risk of germ cell tumour is higher than in CAIS; therefore, an early gonadectomy or an orchidopexy is indicated. Optimal hormone replacement therapy (HRT) is necessary for long-term health. The risks of osteopenia and of regimen osteoporosis are higher, ESPECIALLY in patients with early gonadectomy. Infertility is the rule in CAIS and PAIS. A few mutations do not affect fertility detrimentally, and these are responsible for MAIS. In PAIS leading to a predominantly male phenotype or ambiguous genitalia, multiple surgical procedures for gynaecomastia and/or hypospadias are required. Some small studies have found a higher risk of obesity, hyperlipidaemia and impaired insulin sensitivity. Psychological support is essential, as the prevalence of psychiatric disorders is increased. In conclusion, the diagnosis of AIS has long-term consequences for which shared decision-making (physicians, patients, parents) is appropriate.

A critical role for estrogen signaling in penis development.

Hypospadias, a developmental defect of the penis, is one of the most common congenital malformations in humans. Its incidence has rapidly increased over recent decades, and this has been largely attributed to our increased exposure to endocrine-disrupting chemicals. Penis development is primarily an androgen-driven process; however, estrogen and xenoestrogens are known to affect penis development in both humans and mice. Here, we investigated the role of estrogen in the developing penis. Using a novel penis culture system, we showed that exogenous estrogen directly targets the developing penis in utero to cause hypospadias. In addition, we also uncovered an unexpected endogenous role for estrogen in normal postnatal penis development and showed that a loss of estrogen signaling results in a mild hypospadias phenotype, the most common manifestation of this disease in humans. Our findings demonstrated that both androgen and estrogen signaling are intrinsically required for normal urethral closure. These findings confirmed that penis development is not an entirely androgen-driven process but one in which endogenous estrogen signaling also plays a critical role.-Govers, L. C., Phillips, T. R., Mattiske, D. M., Rashoo, N., Black, J. R., Sinclair, A., Baskin, L. S., Risbridger, G. P., Pask, A. J. A critical role for estrogen signaling in penis development.