Opioids and pediatric urology: A prospective study evaluating prescribing habits and patient postoperative pain and narcotic utilization.

INTRODUCTION: Few pediatric urologists believe patients require a majority of the doses of opioids prescribed to them postoperatively. Seeking a better understanding of postoperative pain and analgesia in pediatric urology patients may help reduce opioid over prescription while still adequately managing postoperative pain. OBJECTIVE: We sought to better understand: 1) the postoperative pain levels experienced by pediatric urology patients, 2) the factors that correlate with postoperative pain and number of opioids consumed following pediatric urologic procedures, and 3) the patients who do not require opioids after surgery. STUDY DESIGN: Pediatric patients undergoing circumcision, inguinal hernia repair, orchidopexy, or hypospadias repair were eligible to participate. Patients were enrolled in the prospective cohort on the day of the procedure. For each of the first 7 postoperative days, patients' parents completed a text message-based questionnaire, quantifying their child's pain level and the doses of pain medication the child consumed. RESULTS: 165 participants were enrolled. 57 patients underwent circumcision, 54 underwent orchiopexy, 32 underwent hypospadias repair, and 22 underwent inguinal hernia repair. For all procedure types, pain scores (p < 0.01) and doses of oxycodone consumed were highest on postoperative day one and steadily declined thereafter. Overall, average 7-day pain score (2.02; 0.86-5.14) and doses of narcotics consumed (3.50; 0-5) were low. Patients in each surgical subgroup were prescribed narcotics in excess of what was consumed. There was an average excess of 10.9 doses (0-39.0) for hypospadias repair, 8.6 (1.0-30.0) for circumcision, 9.0 (3.0-21.0) for inguinal hernia repair, and 6.1 (0-22.0) for orchiopexy. DISCUSSION: Overall, reported pain scores and number of narcotics consumed were low regardless of surgery type. Opioids were overprescribed regardless of surgery type. CONCLUSIONS: Our findings indicate that level of pain and opioid use varies by procedure type, but that number of narcotics prescribed greatly exceeds number needed.

Is parenteral antibiotic prophylaxis associated with fewer infectious complications in stented, distal hypospadias repair?

INTRODUCTION: Judicious use of antibiotics for surgical prophylaxis is important for reducing antimicrobial resistance while preventing infectious surgical complications. In the setting of pediatric distal hypospadias repairs, it is unclear if antibiotic surgical prophylaxis is beneficial. OBJECTIVE: The purpose of this study was to compare rates of infectious complications in pediatric subjects undergoing distal hypospadias repair who received any peri-operative antibiotics to those who did not. STUDY DESIGN: This was a review of a retrospective cohort from a database of individuals undergoing hypospadias repairs evaluating whether they received peri-operative or post-operative antibiotic prophylaxis and determining the rate of infectious complications in those who did compared to those who did not receive antibiotic prophylaxis. Infectious complications were defined as surgical site infection (SSI) or urinary tract infection (UTI). RESULTS: There was no significant difference in infectious complication rates between individuals who received peri-operative parenteral antibiotic prophylaxis and those who did not. All subjects with infectious complications received post-operative oral antibiotic prophylaxis. There was one instance of C. difficile infection in a subject who received peri-operative parenteral antibiotics. DISCUSSION: Reducing antibiotic utilization without increasing infectious surgical complications is important in safely reducing antimicrobial resistance. In this study of pediatric distal hypospadias repair, peri-operative antibiotics did not demonstrate a clear benefit and post-operative oral antibiotics demonstrated no benefit in preventing infectious complications. Other studies evaluating peri- and post-operative antibiotics for pediatric hypospadias repair have also failed to demonstrate a benefit for antibiotics in preventing infections. Practitioners should reconsider the use of antibiotics in this setting. CONCLUSION: Routine antibiotic prophylaxis does not appear beneficial for preventing infectious complications following uncomplicated, stented pediatric distal hypospadias repairs.

Inclusion of surgical antibiotic regimens in pediatric urology publications: A systematic review.

BACKGROUND: Perioperative antibiotics prevent infections after surgery. Guidelines for antibiotic use allow the surgeon to balance the risks of adverse events and drug resistance with the benefit of reduced infection rates. However, due to a lack of evidence-based guidelines within pediatric urology, antibiotic practices vary widely. We performed a systematic literature review to investigate when and how authors report their antibiotic usage and infectious outcomes. Our aim was to analyze the available data on perioperative antibiotics and infection rates within pediatric urology. METHODS: This systematic review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A search strategy was devised to identify reports of pediatric urology surgery and use of antibiotics or infectious outcomes. Embase and Medline were queried with no year restrictions with subject heading terms to identify publications on common pediatric urology surgeries. The procedures studied were hypospadias repair, pyeloplasty, orchidopexy, ureteral reimplant, and circumcision. Two independent reviewers screened all titles and abstracts, followed by relevant full texts, for eligibility. Articles were included if the procedure was performed on the majority of study patients, the procedure was performed by urologic surgeons, and the population studied was a pediatric population defined as 0-18 years of age. Case reports, meta-analyses, and editorials were excluded. Data was extracted by one independent reviewer into a preformatted database. Collected data included journal type, date of publication, patient demographics, preoperative and postoperative antibiotic details including regimens, and infection outcomes. The primary outcome was reporting of antibiotic use preoperatively or postoperatively. Secondary outcomes included: reporting of infection, antibiotic class and dosage. Since all studies were diverse, only qualitative analysis was conducted. RESULTS: We identified 1483 publications with 297 meeting inclusion criteria. Of these, 9% reported their use of preoperative antibiotics, and 34% reported their use of postoperative antibiotics. Only 6% of studies reported the specific antibiotic class, 15% reported duration, and 1% reported dosage and frequency. Infection outcomes were reported in 58% of studies. Only 57% of studies that reported on infection outcomes described their antibiotics practices. CONCLUSIONS: Surgical antibiotic regimens and infection outcomes are infrequently included in pediatric urology studies, limiting the data available for development of evidence-based guidelines. Routine incorporation of antibiotic regimens, infection outcomes and adverse events in the pediatric urology literature will increase our ability to identify indications for antibiotics. Reporting of perioperative antibiotic outcomes in pediatric urology procedures will allow the eventual development of strong evidence-based guidelines.

Effects of pre- and post-pubertal dihydrotestosterone treatment on penile length in 5α-reductase type 2 deficiency.

Steroid 5α-reductase type 2 deficiency (5αRD2) is a congenital disorder of sex development caused by impairment of conversion from testosterone (T) to 5α-dihydrotestosterone (DHT). DHT deficiency leads to various degrees of undervirilized external genitalia including micropenis, primarily correlated with mutations of the SRD5A2 gene that encodes 5α-reductase type 2. Four Japanese boys with isolated micropenis were diagnosed as 5αRD2 by elevated ratios of serum T/DHT, and decreased ratios of urinary 5α/5ß-reduced steroid metabolites. Genetic analyses for SRD5A2 identified that the four patients shared a hypomorphic mutation R227Q that has a residual activity related to the mild-form of 5αRD2. For prepubertal micropenis, DHT was transdermally applied to the four patients at the ages of 4-11 year, increasing a median of stretched penile lengths (SPLs) from 2.6 cm (-2.5 SD) to 4.4 cm (-0.2 SD). Nevertheless, the post-pubertal penile growth was apparently retarded, despite normal levels of T secreted from well-developed testes. The second course of DHT treatment underwent at ages of 12-18 year, but unable to normalize SPLs at a range of 6.0 to 7.0 cm (-3.4 to -2.4 SD). The prostate volumes of two patients were variable at 8.1 and 21 cm3, and a sperm cell count of one patient was normal as young adult. DHT treatment contributes to development of the penis and prostate, which are favorable for the potential fertility of 5αRD2 adults. Meanwhile, the retarded penile growth and a risk of prostate overgrowth may complicate the post-pubertal management with DHT for 5αRD2 males.

Topical estradiol increases epidermal thickness and dermal collagen of foreskin prior to hypospadia surgery - Randomized double blinded controlled trial.

INTRODUCTION: The use of preoperative topical testosterone stimulation prior to hypospadias correction aims to increase penile size and achieve better surgical results. Topical estradiol has been shown to improve the quality of skin in other sites, but its use in boys with hypospadia has not yet been elucidated. OBJECTIVE: This study aims to evaluate the primary effects in epidermal thickness and collagen distribution of estradiol compared to testosterone and placebo in skin of prepuce before hypospadia surgery. MATHERIALS AND METHODS: Patients were randomized into three groups according to the topical hormone used: TG: Testosterone ointment; EG: Estradiol ointment; CG: Neutral base ointment. Fragments of foreskin were excised, fixed and then sectioned for histology. For each sample, epidermal thickness and dermal collagen expression was measured by specific computer analysis, P-values of <0.05. RESULTS: Thirty-three patients with a mean age of 4.01 ± 2.92 years were included. Hypospadia classification was similar in all three groups. Mean epidermal thickness and collagen type I expression in EG were greater than those of the other groups. Collagen type III expression was similar in all groups. DISCUSSION: Foreskin has a fundamental role in many techniques of hypospadias surgery and can be used either as a graft or a flap in the correction of the penile defect. Increase of epidermal thickness and dermal collagen observed in the present study has already been related to use of estradiol in other skin sites, but not yet in foreskin. Further studies are needed to evaluate the real significance of these findings in boys with hypospadias. CONCLUSION: Use of topical estradiol before hypospadias surgery lead to greater epidermal thickness and increases dermal collagen expression in foreskin.

The comparison of the effect of phenylephrine and epinephrine on penile spongy tissue in rats after experimental hypospadias surgery: a quantitative stereological study.

BACKGROUND: Many factors including vasoconstrictor agents can interfere with wound healing process. This study aimed to compare the histopathological outcome of injection of two sympathomimetic drugs used during urologic surgery, including phenylephrine and epinephrine, on the structure of spongy tissue and urethra in a rat model of experimental hypospadias repair using stereological methods. METHODS: Male rats were allocated into three groups. The first group underwent surgery without using any agents. The second and third groups underwent surgery with diluted phenylephrine (1:5000) and diluted epinephrine (1:100000) injection in the urethral plate before operation, respectively. Quantitative histological evaluation of all penises was performed after 3 weeks. RESULTS: The results indicated no significant differences among the three groups regarding the vessels and urethral lumen and epithelium. However, the volumes of the spongy tissue and collagen bundles and the number of fibroblasts were significantly higher (35-55%) in surgery + phenylephrine and surgery + epinephrine groups in comparison to the surgery group (p < 0.05), with no preferences. CONCLUSIONS: Hypospadias repair using phenylephrine and epinephrine injection showed no adverse effects. Furthermore, they might lead to better postoperative structural outcomes without any preferences. However, further experimental and human studies are required to draw a firm conclusion.

The effect of intraurethral dexpanthenol in hypospadias repair: experimental rabbit study.

INTRODUCTION: In this study, the authors aimed to research the histopathologic effects of intraurethral use of dexpanthenol for hypospadias repair. Dexpanthenol is a derivative of pantothenic acid, a B complex vitamin. Pantothenic acid is a molecule contributing in the structure of coenzyme A. It decreases the release of myeloperoxidase from granulocytes and inhibits the formation of free oxygen radicals, and it exhibits an anti-inflammatory effect by increasing mitotic activity. OBJECTIVE: The objective of this study is to evaluate the use of dexpanthenol after a tubularized incised plate urethroplasty (TIP) on wound healing, inflammation, and fibrosis. STUDY DESIGN: In this study, 18 healthy male New Zealand white rabbits weighing 2500-3000 g were used. The 18 rabbits were randomly divided into 3 groups. For the hypospadias model, rabbits had a urethral catheter inserted in the urethra and a ventral midline incision was made from the glans tip to the central line of the penis. Afterward, the incision was closed with Vicryl (7/0) using the continuous suture technique, and urethroplasty was completed. For fourteen days, group I had 0.9% saline solution administered intraurethrally twice per day with a 22G catheter sleeve (control group), group II had one dose of 500 mg/kg dexpanthenol (Bepanthene®; Bayer Turk Chemical Industry Limited Company, Turkey) ampoule and one dose of saline solution administered in the same way, and group III had two doses of 500 mg/kg dexpanthenol ampoule administered. On the fifteenth day, the penis was degloved and rabbits had penectomy performed with samples sent to the pathology department for histopathological assessment. RESULTS: The degree of fibrosis and inflammation in group I (control group) was more severe than groups II and III. The differences between groups I and II were statistically significantly different for both fibrosis and inflammation (P = 0.018 and P = 0.041, respectively). The differences between groups I and III were also statistically significantly different for both fibrosis and inflammation (P = 0.019 and P = 0.011, respectively). Groups II and III were not different significantly for fibrosis and inflammation (P > 0.05). DISCUSSION: This study shows that intraurethral dexpanthenol application has positive effects on fibrosis and inflammation. The main limitations of the study are that the hypospadias model was created surgically and long-term follow-up for fistula formation was not assessed. CONCLUSIONS: Administration of intraurethral dexpanthenol after hypospadias repair has positive effects on fibrosis and inflammation.

Renal Subcapsular xenografing of human fetal external genital tissue - A new model for investigating urethral development.

In this paper, we introduce our novel renal subcapsular xenograft model for the study of human penile urethral and clitoral development. We grafted fifteen intact fetal penes and clitorides 8-11 weeks fetal age under the renal capsules of gonadectomized athymic mice. The mice were treated with a subcutaneous pellet of dihydrotestosterone (DHT), diethylstilbestrol (DES) or untreated with hormones. Xenografts were harvested after fourteen days of growth and analyzed via serial histologic sectioning and immunostaining for Ki-67, cytokeratins 6, 7 and 10, uroplakin and the androgen receptor. Non-grafted specimens of similar fetal age were sectioned and immunostained for the same antigenic markers. 14/15 (93.3%) grafts were successfully propagated and harvested. The developing urethral plate, urethral groove, tubular urethra, corporal bodies and preputial lamina were easily identifiable. These structures demonstrated robust cellularity, appropriate architecture and abundant Ki-67 expression. Expression patterns of cytokeratins 6, 7 and 10, uroplakin and the androgen receptor in xenografted specimens demonstrated characteristic male/female differences analogous to non-grafted specimens. DHT treatment reliably produced tubularization of nascent urethral and vestibular structures and male patterns of androgen receptor expression in grafts of both genetic sexes while estrogenic or hormonally absent conditions reliably resulted in a persistent open urethral/vestibular groove and female patterns of androgen receptor expression. This model's success enables further study into causal pathways by which endocrine-disrupting and endocrine-mimicking substances may directly cause disruption of normal human urethral development or hypospadias.

Use of Hormones, Tissue Factors and Bioengineering in the Management of Hypospadias.

Hypospadiology is a rapidly evolving field. Progress in the understanding of how hormonal therapy affects the growth of the phallus has allowed surgeons to optimize the tissues for surgery. But conflicting data from a number of studies and a lack of consensus on drugs, their dosing, mode of delivery and timing of use means that the creation of protocols is unlikely to happen in the near future. Nonetheless, there is a hope and the standardization of scientific reporting will make it easier to compare data at the global level. There are reports of the increasing incidence of hypospadias and the etiology is thought to be multifactorial. Although complex interactions between genetic polymorphisms and the environment make it difficult to identify the exact factors responsible for hypospadias, the advent of massively parallel gene sequencing, large scale epigenetic screens and CRISPR technology will definitely ease the process. The knowledge of culprit genes will not only broaden our understanding of embryology and growth but will also enable us to predict and/or modify tissue healing. Advances in tissue engineering are also expected to provide a plethora of biomaterials for urethral reconstruction. The development of this field is directly linked with the elucidation of the processes of proliferation and vascularization coupled with the cataloguing of the growth factors involved. One can safely conclude that the exciting new advances in the field will have far reaching consequences on patient care and counselling.

Echocardiographic evaluation of left ventricular mass index in children with hypospadias after hormonal stimulation with topical testosterone: A randomized controlled trial.

INTRODUCTION: Testosterone is often used in the preoperative period of hypospadias surgery. Previous studies have demonstrated the presence of androgen receptors in cardiac myocytes that can modulate the phenotype. The use of supraphysiological doses of androgens can lead to toxicity on the heart muscle and, in some cases, to left ventricular hypertrophy. This randomized double blind controlled clinical trial aims to evaluate the effect of topical testosterone on left ventricular mass index in boys with hypospadias. MATERIALS AND METHODS: Boys with hypospadias aged 6 months to 9 years were included. Children were divided into two groups: G1 - boys who received testosterone propionate 1% ointment twice a day for 30 days, and G2 - boys receiving placebo ointment in the same regimen. All children were submitted to bi-dimensional echocardiographic evaluation to compare the left ventricular mass index, blood pressure, and body mass index before and after treatment (30 and 90 days). Levels of serum testosterone, LH, and FSH were measured. RESULTS: Thirty-five children were analyzed: 17 in G1 and 18 in G2. No differences were found in left ventricular mass index (left ventricular mass indexed by body surface area) prior to treatment. Left ventricular mass index was 59.21 ± 11.91 g/m2 in G1 and 55.12 ± 8.29 g/m2 in G2 (p = 0.244) after 30 days of treatment, and 61.13 ± 11.69 g/m2 in G1 and 62.84 ± 35.99 g/m2 in G2 (p = 0.852) after 90 days. Serum testosterone levels were 12 (7-80) ng/dL in G1 and 5 (5-7) ng/dL in G2 (p = 0.018) after 30 days of treatment, and 10 (5-11) ng/dL in G1 and 5 (4-5) ng/dL in G2 (p = 0.155), after 90 days (Figure). There was a small increase in systolic blood pressure (SBP) after 30 days (83.82 ± 7.18 mmHg) in the group who receive testosterone (G1) compared with controls (77.5 ± 6.69 mmHg) (p = 0.010). After 90 days, SBP levels returned to basal levels in G1 (82.35 ± 5.62 mmHg) and in G2 (81.38 ± 4.79 mmHg) (p = 0.588). CONCLUSION: Topical testosterone can be considered safe in the preoperative period of children with hypospadias with no risk of left ventricular hypertrophy. An increase in systolic blood pressure occurs while using testosterone but it is transitory, returning to normal levels after 90 days.

Impact of preoperative hormonal stimulation on postoperative complication rates after hypospadias repair: a meta-analysis.

INTRODUCTION: To improve the surgical outcome of hypospadias repair surgery, preoperative hormonal stimulation (PHS) has been proposed. We conducted a meta-analysis to evaluate the impact of preoperative hormonal stimulation (PHS) treatment on complication rates following hypospadias repair surgery. EVIDENCE ACQUISITION: A comprehensive literature search up to June 1st, 2015 was carried out for relevant studies. After literature identification and data extraction, relative ratio (RR) was calculated to compare postoperative complication rates. Heterogeneity among individual studies was tested using the Cochran χ2 Q test and quantified by calculating the I2 index. Meta-regression was applied to find potential affective factors. EVIDENCE SYNTHESIS: Overall, 428 patients from 6 studies had undergone primary hypospadias repair, of which 171 (39.95%) received some form of PHS with human chorionic gonadotropin (HCG), dihydrotestosterone (DHT) or testosterone (T). They underwent three different types of surgical techniques, including onlay island flap (N.=277), tubularized incised plate (N.=99) and Koyanagi urethroplasty (N.=52). These 6 studies classified the complication rates based on PHS. The relative ratio (RR) for a complication occurring following PHS use was 1.18 (95% CI: 0.70-2.00, Z=0.91, P=0.539). Significant heterogeneity (I2=47.1%, P=0.092) among various research literature was found and meta-regression was undertaken for the heterogeneity, but surgical technique, mean age of patients at time of surgery, types of PHS and the quality of studies were not the cause of heterogeneity. CONCLUSIONS: Use of T, DHT and HCG prior to hypospadias repair does not appear to increase the incidence of postoperative complications, but further investigation is needed.

Biometry of the hypospadic penis after hormone therapy (testosterone and estrogen): A randomized, double-blind controlled trial.

INTRODUCTION: The use of preoperative hormonal stimulation before hypospadias surgery aims to increase penile size and achieve better surgical results; however, the rules are not clear in the literature. We evaluated the effects of topical testosterone and estrogen in the hypospadic penis regarding biometric measures, side effects, and serum hormonal levels. To our knowledge, this is the first study using estradiol prior to hypospadias surgery. PATIENTS AND METHODS: Sixty-nine children with hypospadias were randomly divided into three study groups: a control group (CG) of 17 children given placebo cream; a testosterone group (TG) of 28 children who used 1% testosterone propionate; and an estradiol group (EG) of 24 children using 0.01% estradiol. All subjects applied the topical ointment on the entire penis, twice daily for 30 days before surgical correction. Biometric evaluation of the penis included penile length and diameter, glans diameter, distance from the urethral meatus to the tip, and the width of the urethral plate. These measurements as well as serum hormone level, and side effects were evaluated prior to hormone use, and 30 and 90 days after. RESULTS: After 30 days an increase in penile diameter and length and diameter of the glans were observed in TG (p < 0.05). The width of the urethral plate and distance from meatus to the tip increased in TG, although not significantly. The most frequent side effects were appearance of pubic hair and darkening of the genital skin, mainly in TG, but these were transient and disappeared after 90 days of treatment. No significant variations were seen in serum hormonal levels (Table). CONCLUSION: As in previous studies, an increase in penile length and diameter, and glans diameter was observed with the use of testosterone. Proximal urethral plate width and distance from the meatus to the tip of the penis had a tendency to increase also in TG. Estradiol did not change biometric measure of the penis. Few side effects occurred after both hormones, and any that did improved after 90 days follow-up and did not change hormone serum levels. CONCLUSION: Preoperative use of topical testosterone increases penile size, diameter of the penis and glans. The use of estradiol does not change penile biometry. Side effects occur mainly with the use of testosterone and are transient. No significant and persistent hormonal changes were observed.

Meta-analysis of Androgen Insensitivity in Preoperative Hormone Therapy in Hypospadias.

OBJECTIVE: To define androgen insensitivity prevalence in hypospadias patients treated with preoperative hormone therapy. MATERIALS AND METHODS: We searched databases that were published in English and Chinese up to September 10, 2014 for our studies. Eligibility criteria were pre-established. Title, abstract, and full-text screenings were conducted by 2 authors independently. Discrepancies were resolved by consensus. Quality assessment of included studies was completed. Meta-analysis was done when appropriate using R, version 3.1.1 for Windows. Heterogeneity among individual studies was tested using the Cochran chi-square Q test and quantified by calculating the I(2) index. RESULTS: Thirteen of 1278 publications met inclusion criteria and were incorporated into this study. Of 306 patients with preoperative hormone therapy, 25 displayed androgen resistance. Meta-analysis demonstrated that the random-effects model generates a pooled estimate of 7.14% (95% confidence interval [CI], 3.16%-15.31%), whereas the fixed-effect model provides an estimate of 14.61% (95% CI, 10.00%-20.85%). Heterogeneity among included studies was found above medium (I(2) = 67.1% [95% CI, 41.2%-81.6%]; P = .0003]. After exclusion of the heterogeneity, both random-effects and fixed-effect models produce a consistent pooled estimate of 6.95% (95% CI, 0%-47.8%). CONCLUSION: We have defined that the prevalence of androgen resistance in hypospadias is 7.14% (95% CI, 3.16%-15.31%). To distinguish isolated hypospadias from patients with androgen insensitivity syndrome, we recommend that androgen-resistant patients should be specifically targeted by molecularly focused diagnosis. Management strategies should include identification of mutations in the androgen receptor gene, timely surgery to repair hypospadias, and long-term follow-up of sexual function and fertility later in life.

Hormone therapy in hypospadias surgery: a systematic review.

Surgical correction of hypospadias is proposed to improve the aesthetic and functional quality of the penis. Hormone therapy preceding surgical correction is indicated to obtain better surgical conditions. However, there is divergence in the literature regarding the hormone therapy of choice, time of its use before surgery, appropriate dose, and route of application. To try to elucidate this matter, an electronic survey of the databases PubMed and Cochrane Central Library was conducted, limited to articles in English published since 1980. Search strategy identified 14 clinical trials that matched the inclusion criteria. Analysis was made in terms of study design, classification of hypospadias, association with chordee and cryptorchidism, type of hormone, route of application, dose and duration of treatment, penile length before and after hormone therapy, glans circumference before and after hormone therapy, adverse effects, and surgical complications. From the trials evaluated it was not possible to determine the ideal neoadjuvant treatment. A preference for use of testosterone was observed. Intramuscular administration seems to have fewer adverse effects than topical treatment. Side effects were seldom described, and treated patients were not followed on a long-term basis. The scarcity of randomized and controlled clinical trials regarding the topic impairs the establishment of a protocol. In conclusion, although preoperative hormone therapy is currently used before hypospadias surgery, its real benefit in terms of improvement of the penis and surgical results has not been defined.

[Recombinant human growth hormone is effective in the postoperative treatment of hypospadias in children].

OBJECTIVE: To evaluate the efficacy of recombinant human growth hormone (rhGH) in the postoperative treatment of hypospadias in children. METHODS: A total of 84 male children with hypospadias treated by surgery were randomly divided into a control and an rhGH group of equal number, the former treated with antibiotics plus hemostatics with usual wound care, while latter, in addition, by subcutaneous injection of rhGH at 0.2 U/kg/d qd before bedtime for 7 days. Then we compared the two groups in the clinical efficacy, urinary symptoms, peripheral WBC count, C-reactive protein (CRP) level, ratio of CD4+ to CD8+ T lymphocytes in the peripheral blood, contents of serum albumin and total protein, and levels of IgM, IgG and IgA in the serum. RESULTS: The total effectiveness rates in the rhGH and control groups were 81.0% and 66.7%, respectively, significantly higher in the former than in the latter (P<0.05). The levels of WBC and CRP in the peripheral blood were increased after treatment, but with no significant difference. The contents of serum albumin and total protein were higher before than after surgery. The levels of IgM, IgG and IgA were markedly elevated in the rhGH group as compared with the control. The ratio of CD4+ to CD8+ was significantly increased while the level of CD8+ remarkably decreased after treatment in comparison with pre-treatment. CONCLUSION: RhGH is effective and safe in the postoperative treatment of hypospadias in children, and its action mechanisms are associated with its promotion of protein synthesis, improvement of negative nitrogen balance and enhancement of immune function.

Does androgen stimulation prior to hypospadias surgery increase the rate of healing complications? - A preliminary report.

OBJECTIVE: Androgens have a positive effect on penile growth in children, but they may also have a repressive effect on the healing process. The aim of this prospective study was to compare the outcomes of onlay urethroplasty with and without preoperative androgen stimulation in patients with severe hypospadias. PATIENTS AND METHOD: Of 300 severe hypospadias cases treated at a single institution, 126 operated on by the same surgeon had complete follow-up data, and 30 of these received preoperative androgen treatment (human chorionic gonadotrophin and/or systemic testosterone) 1-24 months before surgery. RESULTS: Thirty-five patients presented with a complication (27.7%) of whom 26 (20.6%) had a fistula or dehiscence. Among patients on androgen stimulation there was a 30% healing complication rate (9/30) whereas for those without this was 17.7% (17/96). When androgenic treatment was given > 3 months prior to surgery the healing complication rate was 21.7% (5/23), and when < 3 months prior to surgery the rate reached 57% (4/7). Mean follow up was 41 months (10-97). CONCLUSION: Although the numbers were too small in this series to reach statistical significance, the tissular interactions of androgens in the healing process reported by dermatologists should alert the hypospadiologists and lead to a further prospective study to define the optimal protocol for stimulation of the penis in specific cases without affecting outcome.

Fkbp52 regulates androgen receptor transactivation activity and male urethra morphogenesis.

Hypospadias is a common birth defect in humans, yet its etiology and pattern of onset are largely unknown. Recent studies have shown that male mice with targeted ablation of FK506-binding protein-52 (Fkbp52) develop hypospadias, most likely due to actions of Fkbp52 as a molecular co-chaperone of the androgen receptor (AR). Here, we further dissect the developmental and molecular mechanisms that underlie hypospadias in Fkbp52-deficient mice. Scanning electron microscopy revealed a defect in the elevation of prepucial swelling that led to the onset of the ventral penile cleft. Interestingly, expression of Fkbp52 was highest in the ventral aspect of the developing penis that undergoes fusion of the urethral epithelium. Although in situ hybridization and immunohistochemical analyses suggested that Fkbp52 mutants had a normal urethral epithelium signaling center and epithelial differentiation, a reduced apoptotic cell index at ventral epithelial cells at the site of fusion and a defect of genital mesenchymal cell migration were observed. Supplementation of gestating females with excess testosterone partially rescued the hypospadic phenotype in Fkbp52 mutant males, showing that loss of Fkbp52 desensitizes AR to hormonal activation. Direct measurement of AR activity was performed in mouse embryonic fibroblast cells treated with dihydrotestosterone or synthetic agonist R1881. Reduced AR activity at genes controlling sexual dimorphism and cell growth was found in Fkbp52-deficient mouse embryonic fibroblast cells. However, chromatin immunoprecipitation analysis revealed normal occupancy of AR at gene promoters, suggesting that Fkbp52 exerts downstream effects on the transactivation function of AR. Taken together, our data show Fkbp52 to be an important molecular regulator in the androgen-mediated pathway of urethra morphogenesis.