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Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.

Significance Androgen is essential for the masculinization of external genitalia such as the organ size and the male-type urethra in mammals. However, the genes downstream of androgen, which are responsible for these masculinization processes, have not been identified. Here, we show v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( Mafb ) as an essential masculinization gene for embryonic urethral formation. Mafb expression is prominent in developing male external genitalia, driving masculinization of embryonic urethral formation in an androgen-dependent manner. External genitalia of Mafb KO males exhibit urethral defects, giving insight into human hypospadias. The current findings indicate that Mafb is a crucial mediator of urethral masculinization and is a possible new candidate gene for hypospadias derived from embryonic abnormalities. Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor ( Ar ) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.

This article reviews the current evidence and knowledge of the aetiology of hypospadias. Hypospadias remains a fascinating anomaly of the male phallus. It may be an isolated occurrence or part of a syndrome or field defect. The increasing use of assisted reproductive techniques and hormonal manipulation during pregnancy may have been associated with an apparent rise in the incidence of hypospadias. Genetic studies and gene analysis have suggested some defects that could result in hypospadias. New light has also been thrown on environmental factors that could modulate candidate genes, causing altered development of the male external genitalia.

46,XY disorders of sex development (DSD) refer to a wide range of abnormal genitalia, including hypospadias, which affects ∼0.5% of male newborns. We identified three different nonsense mutations of CXorf6 in individuals with hypospadias and found that its mouse homolog was specifically expressed in fetal Sertoli and Leydig cells around the critical period for sex development. These data imply that CXorf6 is a causative gene for hypospadias.

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

Hypospadias is the most common congenital anomaly of the penis. The problem usually develops sporadically and without an obvious underlying cause. The ectopically positioned urethral meatus lies proximal to the normal site and on the ventral aspect of the penis, and in severe cases opens onto the scrotum or perineum. The foreskin on the ventral surface is deficient, while that on the dorsal surface is abundant, giving the appearance of a dorsal hood. Chordee is more common in severe cases. Cryptorchidism and inguinal hernia are the most common associated anomalies. The frequency of associated anomalies increases with the severity of hypospadias. For isolated anterior or middle hypospadias, laboratory studies are not usually necessary. Screening for urinary tract anomalies should be considered in patients with posterior hypospadias and in those with an anomaly of at least one additional organ system. The ideal age for surgical repair in a healthy child is between 6 and 12 months of age. Most cases can be repaired in a single operation and on an outpatient basis. Even patients with a less than perfect surgical result are usually able to enjoy a satisfactory sexual life. Edited by Prof. Niels Jorgensen

Background Hypospadias are among the most common genital malformations. Langerhans Cells (LCs) play a pivotal role in HIV and HPV infection. The migration of LC precursors to skin coincides with the embryonic period of hypospadias development and genetic alterations leading to the formation of hypospadias impact the development of ectodermally derived tissues. We hypothesized that this might be associated with a difference in frequency or morphology of epidermal and dermal LCs in hypospadias patients. Methods A total of 43 patients from two centers were prospectively included into this study after parental consent and ethics approval. Epidermal and dermal sheets were prepared from skin samples of 26 patients with hypospadias, 13 patients without penile malformations and 4 patients with penile malformations other than hypospadias. Immunofluorescence staining of sheets was performed with anti-HLA-DR-FITC and anti-CD207/Langerin-A594 antibodies. Skin sections from 11 patients without penile malformation and 11 patients with hypospadias were stained for Langerin. Frequencies as well as morphology and distribution of epidermal and dermal LCs on sheets and sections were microscopically evaluated. Cell counts were compared by unpaired t-tests. Results There was no difference in frequency of epidermal LCs, Neither on sheets (873 ± 61 vs. 940 ± 84LCs/mm 2 , p  = 0.522) nor on sections (32 ± 3 vs. 30 ± 2LCs/mm 2 , p  = 0.697). Likewise, the frequency of dermal LCs (5,9 ± 0,9 vs. 7.5 ± 1.3LCs/mm 2 , p  = 0.329) was comparable between patients with hypospadias and without penile malformation. No differences became apparent in subgroup analyses, comparing distal to proximal hypospadias ( p  = 0.949), younger and older boys ( p  = 0.818) or considering topical dihydrotestosterone treatment prior to surgery ( p  = 0.08). The morphology of the LCs was not different comparing hypospadias patients with boys without penile malformations. Conclusions LCs are present in similar frequencies and with a comparable morphology and distribution in patients with hypospadias as compared to children without penile malformations. This suggests that patients with hypospadias are not different from patients with normal penile development considering this particular compartment of their skin immunity.

The surgical management of primary severe hypospadias remains controversial. In this Review, Castagnetti and El-Ghoneimi discuss the various preoperative, intraoperative and postoperative factors that might influence the outcome of surgery, and assess the possible advantages and drawbacks of such interventions. Hypospadias is one of the most common congenital malformations of the male genitalia. Severe cases present with associated curvature greater than 30° and the meatus opening proximally to the penoscrotal junction. The perioperative management of patients with primary severe hypospadias is variable. Systematic evaluation of the upper urinary tract and the search for enlarged prostatic utricles seem unnecessary in patients with isolated primary severe hypospadias, and should be limited to severe cases with associated extraurinary malformations. Detection of a disorder of sex development is key for gender assignment and prognosis, but the identification of cases warranting a full work-up and the influence of such a diagnosis on the success of hypospadias repair is controversial. Preoperative hormonal stimulation allows for penile growth irrespective of the administration route. Associated morbidity is minimal, but its influence on the success of surgery is still unknown. An age of 6–18 months is generally recommended for surgery, but no trial data support this policy. Second-layer coverage of the urethroplasty and postoperative urinary drainage seem to reduce the complications of surgery, whereas postoperative antibiotic prophylaxis and type of dressing have minimal impact on surgical success. Overall, most interventions are based on weak evidence, and their influence on the outcomes of repair is ill-defined. Clinicians should be made aware of the evidence supporting any single intervention in order to standardize their management policies. We hope the issues outlined here will prompt researchers to design new studies to address the clinically relevant questions. Key Points Systematic evaluation of the upper urinary tract and investigation for enlarged prostatic utricles seem unnecessary in patients with isolated primary severe hypospadias Diagnosis of a disorder of sex development is key, but the identification of cases warranting a full work-up and the influence of diagnosis on the success of surgery are controversial Preoperative hormonal stimulation allows for penile growth irrespective of the administration route; associated morbidity is minimal, but its influence on the success of surgery is still unknown An age of 6–18 months is generally recommended for surgery, but no trial data support this policy Second-layer coverage of the urethroplasty and postoperative urinary drainage seem to reduce the complications of surgery Postoperative antibiotic prophylaxis and type of dressing have minimal impact on the success of surgery

Background: Reported rises in the prevalence of hypospadias and other abnormalities of the male reproductive system may be a result of exposure to endocrine disrupting chemicals. Aims: To analyse the relation between risk of hypospadias and maternal occupation, particularly with regard to exposure to potential endocrine disrupting chemicals (EDCs). Methods: Data (1980–96) from the National Congenital Anomaly System (NCAS) were used to analyse the proportion of all congenital anomaly cases (n = 35 962) which were notified with hypospadias (n = 3471) by occupational codes (348 individual job titles) and by categories of exposure to potential EDCs from a job exposure matrix. Results: Five individual occupations (of 348) showed nominally statistically significant excesses, none of which had possible or probable exposure to potential EDCs. Odds ratios for “possible” or “probable” compared to “unlikely” exposure to potential EDCs did not show statistically significant increases in any of the EDC categories after adjustment for social class of the mother and father, nor was there evidence of an upward trend in risk with likelihood of exposure. In the 1992–96 time period odds ratios were increased for hairdressers (the largest group exposed to potential EDCs) and for probable exposure to phthalates (of which hairdressers form the largest group) before social class adjustment. Conclusions: There was little evidence for a relation between risk of hypospadias and maternal occupation or occupational exposure to potential EDCs, but as the exposure classification was necessarily crude, these findings should be interpreted with caution.

To categorize variant persistent müllerian-duct derivatives (MDD) in males and determine their related clinical presentations for further management, five male patients with retained MDDs from abnormal müllerian remnants were studied. They comprised one patient with persistent müllerian-duct syndrome, one with transverse testicular ectopia, two with mixed gonadal dysgenesis, and one with a müllerian-duct cyst. Removal of persistent müllerian-duct structures and genitoplasty were done in selected patients. Categorization of patients with persistent MDDs permits further understanding of the pathogenesis and facilitates the choice of treatment.