Vascular dysfunction and increased cardiovascular risk in hypospadias.

AIMS: Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease. METHODS AND RESULTS: Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5-11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7-114.3, P = 0.02). CONCLUSION: Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males.

Effects of Sex Hormones on Vascular Reactivity in Boys With Hypospadias.

BACKGROUND: Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear. AIMS: We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias. METHODS: Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17ß-estradiol, dihydrotestosterone (DHT), and testosterone. RESULTS: In controls, testosterone and 17ß-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P < .0002; and 83.74 vs 110.2 after estradiol, P = .02). 17ß-estradiol reduced vasorelaxation in arteries from controls (Emax: 10.6 vs 15.6 to acetylcholine, P < .0001; and Emax: 14.6 vs 20.5 to sodium nitroprusside, P < .0001). In hypospadias, testosterone (Emax: 137.9 vs 107.2, P = .01) and 17ß-estradiol (Emax: 156.9 vs 23.6, P < .0001) reduced contraction. Androgens, but not 17ß-estradiol, increased endothelium-dependent and endothelium-independent vasorelaxation in cases (Emax: 77.3 vs 51.7 with testosterone, P = .02; and vs 48.2 with DHT to acetylcholine, P = .0001; Emax: 43.0 vs 39.5 with testosterone, P = .02; and 39.6 vs 37.5 with DHT to sodium nitroprusside, P = .04). CONCLUSION: In healthy boys, testosterone and 17ß-estradiol promote a vasoconstrictor phenotype, whereas in boys with hypospadias, these sex hormones reduce vasoconstriction, with androgens promoting vasorelaxation. Differences in baseline artery function may therefore be sex hormone-independent and the impact of early-life variations in androgen exposure on vascular function needs further study.

Gonadal Function in Boys with Bilateral Undescended Testes.

Background: Bilateral undescended testes (BUDT) may be a marker of an underlying condition that affects sex development or maturation. Aims: To describe the extent of gonadal dysfunction in cases of BUDT who had systematic endocrine and genetic evaluation at a single tertiary pediatric center. Methods: A retrospective review was conducted of all boys with BUDT who had endocrine evaluation between 2008 and 2021 at the Royal Hospital for Children, Glasgow (RHCG). Continuous variables were analyzed using Mann-Whitney U and non-continuous variables using Fisher's exact, via Graphpad Prism v 8.0. Multivariable logistic regression was used to identify any associations between groups. A P < .05 was considered statistically significant. Results: A total of 243 bilateral orchidopexies were performed at RHCG between 2008 and 2021. Of these 130 (53%) boys were seen by the endocrine team. The median (range) age at first orchidopexy was 1 year (0.2, 18.0) with 16 (12%) requiring re-do orchidopexy. The median External Masculinization Score of the group was 10 (2, 11) with 33 (25%) having additional genital features. Of the 130 boys, 71 (55%) had extragenital anomalies. Of the 70 who were tested, a genetic abnormality was detected in 38 (54%), most commonly a chromosomal variant in 16 (40%). Of the 100 who were tested, endocrine dysfunction was identified in 38 (38%). Conclusion: Genetic findings and evidence of gonadal dysfunction are common in boys who are investigated secondary to presentation with BUDT. Endocrine and genetic evaluation should be part of routine clinical management of all cases of BUDT.

Increased occurrence of disorders of sex development, prematurity and intrauterine growth restriction in children with proximal hypospadias associated with undescended testes.

PURPOSE: Proximal hypospadias represents 20% of hypospadias cases, which are considered to have a higher incidence of associated urological, nonurological, developmental and sexual development disorders, and chromosomal anomalies. We compared associated anomalies in boys with proximal hypospadias and undescended testis with those in boys with proximal hypospadias and descended testes. MATERIALS AND METHODS: We reviewed the medical records of 69 boys who underwent 2-stage hypospadias repair for proximal hypospadias at a single institution during the 11-year period of 2001 to 2011. Collected data included demographics, birth history, associated urological and extra-urological anomalies, karyotype analysis and gonad palpability. Patients were divided into group 1-those with proximal hypospadias and undescended testis, and group 2-those with proximal hypospadias and descended testes. Statistical analysis was performed using the 2-tailed Fisher exact test. RESULTS: There were 17 patients (25%) in group 1 with a median age of 2.2 years and 52 in group 2 (75%) with a median age of 2 years. Children in group 1 had a higher incidence of XY nondysgenetic testicular sexual development disorder (8 vs 11, p = 0.06), premature birth (9 vs 10, p = 0.01) and intrauterine growth restriction (8 each) than children in group 2 (p = 0.01). CONCLUSIONS: Prematurity and intrauterine growth restriction are significantly associated with proximal hypospadias and undescended testis. Also, due to the 28% incidence of an underlying sexual development disorder, male infants with proximal hypospadias should undergo multidisciplinary evaluation.

Bilateral ureteric obstruction secondary to renal papillary necrosis.

A 2-year-old male presented to hospital with a 5-day history of vomiting and pyrexia. He was initially treated with non-steroidal medication as an anti-pyretic. Initial investigations demonstrated a raised urea and creatinine and he was treated with intravenous fluids. Within 24 h he became anuric with progressive renal insufficiency. Ultrasound scan demonstrated minimal bilateral hydronephrosis with debris in the lower pole calyces. The bladder was empty. Cystoscopy and retrograde contrast imaging revealed bilateral ureteric obstruction. Double J stents were inserted and his renal function returned to normal within 4 days. We believe the aetiology to be renal papillary necrosis and bilateral ureteric obstruction secondary to the administration of ibuprofen in association with dehydration.

PUVs are more common in boys with hypospadias.

INTRODUCTION: The association between posterior urethral valves (PUVs) and hypospadias has previously been reported in case reports. After the identification of this twin pathology in a number of patients, a national retrospective review of all patients with this dual diagnosis was performed. PATIENTS AND METHODS: All patients were identified in each centre from surgical databases of prospectively collated information on all surgical procedures. The medical notes were reviewed to ascertain demographics, the type of hypospadias, the mode of presentation of the valves and the outcome. RESULTS: Twenty-eight patients who had the dual diagnosis of hypospadias and PUV between 2002 and 2017 in the four tertiary paediatric centres where specialist paediatric urology is undertaken in our country were identified. Most patients (n = 24) had the valves diagnosed after hypospadias surgery. The median age at the time of hypospadias surgery was 1.4 years (range 1-4 years). There were 12 proximal and 16 mid or distal hypospadias. The commonest presentation was with problems voiding after surgery in 14 cases with a further seven boys who had urinary tract infections. Four patients had a urethro-cutaneous fistula after repair that initiated further assessment. Two boys had distal dehiscence of their repair. There was one boy presented with new onset daytime incontinence. The median time of follow-up after valve incision surgery was 4.9 years (range 0.1-12.3 years). Twenty-two patients (three pre toilet training) had no ongoing urinary symptoms. Twenty-one boys have normal renal function with one patient in stage 3b chronic kidney disease. The incidence of this dual diagnosis in Scotland is estimated at one in 100 cases of hypospadias in the paediatric population. CONCLUSION: The incidence of PUV in boys with hypospadias is estimated at 1% patients.

Predictors of complications following retroperitoneoscopic total and partial nephrectomy.

INTRODUCTION: Recent reports in the literature suggest an increased risk of complications with retroperitoneal as opposed to transperitoneal approach to partial nephrectomy (PN) and total nephrectomy (TN). We are a large unit performing predominantly retroperitoneoscopic PN and TN. We aim to review our outcomes and perform analysis to elucidate the predictors of complications following the retroperitoneal approach for extirpative kidney surgery. METHODS: We performed a single center retrospective review of children undergoing MIMS TN and PN between 2005 and 2015. Variables were tested for association with outcomes using Chi2 and Spearman's Rho correlation. RESULTS: We performed 173 MIMS nephrectomies, 119 total and 54 partial. Median age and weight were 5 years (6 months to 18 years) and 24.9 kg (7.7 to 85 kg) and operative time 147 min. There were 4 conversions and 17 postoperative complications. 19.6% children required further surgery, including 8 completion stumpectomies. Retroperitoneal approach did not have increased risk compared to transperitoneal for need of further surgery. Partial nephrectomy was not associated with higher rate of intraoperative complication or LOS. Predictors of intraoperative complication were vessel closure technique. Associations with need for further surgery were: ESRF, contralateral disease, bladder dysfunction, presence of PD catheter, and need for concomitant procedure. CONCLUSION: Our conversion rate (1.9%) and need for further surgery (13.1%) following the retroperitoneal approach to the kidney are favorable to the literature. Need for reoperation is often associated with the underlying diagnosis and the natural sequelae of the disease process. LEVEL OF EVIDENCE: IV.

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome.

Extra-genital congenital anomalies are often present in cases of hypospadias, but it is unclear whether they have an association with the outcome of hypospadias surgery. The aim of this study was to review all hypospadias cases that had surgery between 2009 and 2015 at a single centre and identify clinical determinants of the surgical outcome. An extra-genital congenital anomaly was reported in 139 (22%) boys and 62 (10%) had more than 1 anomaly. Of the 626 boys, 54 (9%), including 44 with proximal hypospadias, had endocrine as well as limited genetic evaluation. Of these, 10 (19%) had a biochemical evidence of hypogonadism and 5 (9%) had a molecular genetic abnormality. At least 1 complication was reported in 167 (27%) patients, with 20% of complications (most frequently fistula) occurring after 2 years of surgery. The severity of hypospadias and the existence of other anomalies were clinical factors that were independently associated with an increased risk of complications (p < 0.001). In conclusion, complications following surgery are more likely in those cases that are proximal or who have additional extra-genital anomalies. To understand the biological basis of these complications, there is a greater need to understand the aetiology of such cases.

Open versus prone retroperitoneoscopic partial nephrectomy in children: a comparative study.

PURPOSE: To compare the outcomes of open (OPN) and prone retroperitoneoscopic partial nephrectomy (PRPN) in children. MATERIALS AND METHODS: The medical and radiological records of all children undergoing OPN and PRPN over a 6-year period (2002-2008) were reviewed. RESULTS: Thirty-nine (11 boys/28 girls) partial nephrectomies were performed in a single institution. There were 24 OPNs (15 upper, 9 lower) and 15 PRPNs (13 upper, 2 lower) with a median age at surgery of 2.3 years and 3.4 years, respectively. Median duration of surgery was 50 min (range 30-180) for the OPN and 150 min (range 70-205) for the PRPN (P < 0.001). Median postoperative hospital stay was 4 days (range 2-7) for the OPN and 2 days (range 1-5) for the PRPN (P < 0.001). One patient in the OPN underwent a total nephrectomy with a loss of the remaining moiety. In 20 (87%) patients of the OPN group an epidural infusion was administered and four required a morphine infusion, while only five patients in the PRPN group required a morphine infusion. CONCLUSIONS: Open partial nephrectomy had a significantly shorter operative time, but it was associated with a longer postoperative stay and higher analgesia requirements when compared to PRPN.