Development of external genitalia during mini-puberty: is it related to somatic growth or reproductive hormones?

Although hypothalamo-pituitary-gonadal axis is active during mini-puberty, its relationship with somatic growth and the role on the development of external genitalia has not been fully elucidated. We aimed to evaluate the effects of somatic growth and reproductive hormones on the development of external genitalia during mini-puberty. Anthropometric data, pubertal assesment, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), sex-hormone binding globulin (SHBG), estradiol (E2) and inhibin-B, testosterone (T), and anti-Mullerian Hormone (AMH) of healthy infants aged 1-4 months were evaluated. Free sex hormone index was calculated as T/SHBG for boys and E2/SHBG for girls. The mean age of 148 (74 female) infants included in the study was 2.31 ± 0.76 months. Tanner stage 2-3 sex steroid and gonadotropin levels were observed. A statistically significant difference was found between the weight, height, BMI, weight gain and serum FSH, LH, and A4 measurements of girls and boys (p < 0.05). Penile length was associated with weight (r = 0.24, p = 0.03), height (r = 0.25, p = 0.02), and AMH (r = 0.3, p = 0.01), but not with testosterone (p = 0.56 respectively). A negative correlation was found between weight and serum LH (r = - 0.26, p = 0.2) and T/SHBG levels in males (r = - 0.38, p = 0.015 respectively). Weight-SDS was negatively correlated with testosterone in males (r = - 0.25, p = 0.02). Testicular size and breast stage did not correlate with any of the hormonal and anthropometric parameters.  Conclusions: External genitalia in males during mini-puberty is related more to somatic growth rather than reproductive hormones. Similar to pubertal developmental stages, both total and free testosterone are negatively associated with higher weight during mini-puberty. What is Known: • Mini-puberty allows early assessment of HPG axis function in infancy. • There is an inverse relationship between the amount of adipose tissue and circulating testosterone levels in males during puberty and adulthood. • The potential effect of somatic growth and reproductive hormones on external genital development during mini-puberty remains unclear. What is New: • During mini-puberty, males' external genitalia is more related to somatic growth than to reproductive hormones, but this relationship is not observed in girls. • Both total and free testosterone are negatively associated with higher weight during mini-puberty, similar to the pubertal developmental stages.

Characteristic external genitalia in male neonates with 5α-reductase deficiency.

There have been no reports comparing neonatal external genitalia of 5α-reductase deficiency (5αRD) with those of other 46,XY differences of sex differentiation (DSD). This study enrolled 31 Japanese cases of 46,XY DSD whose external genitalia was examined during the neonatal period; four were diagnosed as 5αRD and 15 were defined as non-5αRD by genetic analysis of SRD5A2 or urinary steroid metabolites. We compared the following characteristics between 5αRD and non-5αRD groups, adjusting the severity of undermasculinization of the external genitalia: stretched penile length (SPL), glans width, location of the external urethral opening, and proportion of undescended testis. The external genitalia of all the 5αRD cases were Quigley classification grade 2 or 3. We compared the phenotypes between the four 5αRD cases and 11 non-5αRD cases with grade 2 or 3. The median (range) of SPL in the 5αRD group (14 mm [11-16]) was significantly lower than that in the non-5αRD group (22 mm [15-29]) (p = 0.003). An SPL cut-off value of <15 mm yielded a sensitivity of 50% (95% confidence interval [CI]; 7-93%) and specificity of 100% (95% CI, 72-100%) for discriminating between the groups. The median glans width, location of the external urethral opening, and proportion of undescended testis were not significantly different between the groups. The SPL of 5αRD in Quigley classification grade 2 or 3 was significantly shorter than that of other 46,XY DSDs with the equivalent grade.

Sexual fate of murine external genitalia development: Conserved transcriptional competency for male-biased genes in both sexes.

Testicular androgen is a master endocrine factor in the establishment of external genital sex differences. The degree of androgenic exposure during development is well known to determine the fate of external genitalia on a spectrum of female- to male-specific phenotypes. However, the mechanisms of androgenic regulation underlying sex differentiation are poorly defined. Here, we show that the genomic environment for the expression of male-biased genes is conserved to acquire androgen responsiveness in both sexes. Histone H3 at lysine 27 acetylation (H3K27ac) and H3K4 monomethylation (H3K4me1) are enriched at the enhancer of male-biased genes in an androgen-independent manner. Specificity protein 1 (Sp1), acting as a collaborative transcription factor of androgen receptor, regulates H3K27ac enrichment to establish conserved transcriptional competency for male-biased genes in both sexes. Genetic manipulation of MafB, a key regulator of male-specific differentiation, and Sp1 regulatory MafB enhancer elements disrupts male-type urethral differentiation. Altogether, these findings demonstrate conservation of androgen responsiveness in both sexes, providing insights into the regulatory mechanisms underlying sexual fate during external genitalia development.

Developmental and functional roles of androgen and interactive signals for external genitalia and erectile tissues.

Background: Recent progress in molecular and signal analyses revealed essential functions of cellular signals including androgen and related growth factors such as Wnt regulators for external genitalia (ExG) development and its pathogenesis. Accumulated data showed their fundamental functions also for erectile tissue (corporal body) development and its abnormalities. The current review focuses on such signals from developmental and functional viewpoints. Methods: Experimental strategies including histological and molecular signal analyses with conditional mutant mice for androgen and Wnt signals have been extensively utilized. Main findings: Essential roles of androgen for the development of male-type ExG and urethral formation are shown. Wnt signals are associated with androgen for male-type ExG organogenesis. Androgen plays essential roles in the development of erectile tissue, the corporal body and it also regulates the duration time of erection. Wnt and other signals are essential for the regulation of mesenchymal cells of erectile tissue as shown by its conditional mutant mouse analyses. Stress signals, continuous erection, and the potential of lymphatic characteristics of the erectile vessels with sinusoids are also shown. Conclusion: Reiterated involvement of androgen, Wnt, and other regulatory factors is stated for the development and pathogenesis of ExG and erectile tissues.

Developmental regulation of the male urogenital papilla in the male marine teleost black rockfish, Sebastes schlegelii (Hilgendorf, 1880)†.

The male external genitalia of the black rockfish (Sebastes schlegelii Hilgendorf, 1880) is a fleshy protrusion known as the urogenital papilla (UGP), which functions to deliver sperm into the female reproductive tract for internal fertilization. It is not known which genes regulate the development of the UGP. The aim of this study was to identify key genes that regulate the development of the UGP in black rockfish and to determine the distribution of androgen receptor gene (ar) in the UGP. A total of 26 adult males and 560 juvenile fish were used in the experiment, in which we divided all normally developing juveniles into normal development and androgen groups. We added methyltestosterone solution (100 µg/l) to the androgen group-treated fish tank, soaked for 2 h per day for 38 days, and sampled 5~10 samples each time every 5 days during the culture process. Gene expression changes related to UGP were analyzed with tissue specificity between control and androgen groups during sex differentiation, adult male maturation, and the copulation stage (September to December) using real-time quantitative polymerase chain reaction. The expression of ar was also localized by two-color in situ hybridization in the UGP region of juvenile fish. Androgen treatment enhanced ar expression levels and the ar signal was stronger in the UGP region of both adult breeding fish and androgen-treated juvenile fish. This study provides insights into the regulation of the external genitalia of black rockfish and presents vital information for the artificial breeding of viviparous fish.

The role of p63 in embryonic external genitalia outgrowth in mice.

Embryonic external genitalia (genital tubercle [GT]) protrude from the cloaca and outgrow as cloacal development progresses. Individual gene functions and knockout phenotypes in GT development have been extensively analyzed; however, the interactions between these genes are not fully understood. In this study, we investigated the role of p63, focusing on its interaction with the Shh-Wnt/Ctnnb1-Fgf8 pathway, a signaling network that is known to play a role in GT outgrowth. p63 was expressed in the epithelial tissues of the GT at E11.5, and the distal tip of the GT predominantly expressed the ΔNp63α isoform. The GTs in p63 knockout embryos had normal Shh expression, but CTNNB1 protein and Fgf8 gene expression in the distal urethral epithelium was decreased or lost. Constitutive expression of CTNNB1 in p63-null embryos restored Fgf8 expression, accompanied by small bud structure development; however, such bud structures could not be maintained by E13.5, at which point mutant GTs exhibited severe abnormalities showing a split shape with a hemorrhagic cloaca. Therefore, p63 is a key component of the signaling pathway that triggers Fgf8 expression in the distal urethral epithelium and contributes to GT outgrowth by ensuring the structural integrity of the cloacal epithelia. Altogether, we propose that p63 plays an essential role in the signaling network for the development of external genitalia.

[Outcome, quality of life and functional assessment after perineal and external genitalia gangrene]. / Prise en charge de la gangrène des organes génitaux externes et du périnée : résultats, qualité de vie et évaluation fonctionnelle.

INTRODUCTION: External genitalia gangrene is a well-known uncommon disease; however, mortality remains important. Recent literature focuses on early management. The object of this study was to assess quality of life and disease-specific function, in the medium- and long-term. METHOD: We evaluated retrospectively adult inpatients with external genitalia gangrene who had a surgical debridement between 2010 and 2020 at CHU de Poitiers. Preoperatory FGSI Score was calculated for patients included. In a second phase, surviving patients at 2020 who had agreed to take part in the follow-up were assessed by clinical examination, and asked to complete Short-Form 36 test and two additional disease-specific questionnaire (USP, IIEF5). RESULTS: The patients consisted of 33 men. Mean age was 61.18. Eleven patients (33%) died primarily from external genitalia gangrene. Median FGSI score was 6 (1-13). We were able to reach 11 patients (33%) for secondary clinical revaluation. Time before revaluation was 3months to 8years. All parts of SF-36 were significantly low. Mean USP score was 1.27±2.68/4.54±4.43/0.72±1.84. Nine patients (81%) suffered erectile dysfunction without any sexual intercourse possible. CONCLUSION: Patients with external genitalia gangrene experience severe deterioration of their quality of life. Multidisciplinary healthcare process should systematically be carried out, as so as early screening of vulnerability risks factors, to improve functional outcomes and quality of life.

Single cell transcriptomic analysis of external genitalia reveals complex and sexually dimorphic cell populations in the early genital tubercle.

External genital organs are among the most recognizable sexually dimorphic characters. The penis and clitoris develop from the embryonic genital tubercle, an outgrowth at the anterior margin of the cloaca that undergoes an extensive period of development in male and female embryos prior to the onset of sexual differentiation. In mice, differentiation into the penis and clitoris begins around embryonic day (E)15.5. Current knowledge of cell types that comprise the genital tubercle is limited to a few studies that have fate mapped derivatives of endoderm, mesoderm, and ectoderm. Here we use single cell transcriptomics to characterize the cell populations in the genital tubercles of male and female mouse embryos at E14.5, approximately 24 â€‹h before the onset of sexual differentiation, and we present the first comprehensive atlas of single-cell gene expression during external genital development. Clustering analyses and annotation using marker genes shows 19 distinct cell populations in E14.5 genital tubercles. Mapping of cell clusters to anatomical locations using in situ gene expression patterns revealed granularity of cellular specializations and positional identities. Although E14.5 precedes sexually dimorphic morphogenesis of the genital tubercle, comparative analysis of males and females identified sexual dimorphisms at the single cell level, including male-specific cell clusters with transcriptional signatures of smooth muscle and bone progenitors, both of which are known to be sexually dimorphic in adult genitalia, as well as immune cells. These results provide a new resource for classification of external genital cell types based on gene expression profiles and reveal sex-specific cellular specializations in the early genital tubercle.

Comparative transcriptome analysis identifies crucial candidate genes and pathways in the hypothalamic-pituitary-gonadal axis during external genitalia development of male geese.

BACKGROUND: All birds reproduce via internal fertilization, but only ~3% of male birds possess the external genitalia that allows for intromission. Waterfowl (e.g., duck and goose) are representatives of them, and the external genitalia development of male geese is directly related to mating ability. Notably, some male geese show abnormal external genitalia development during ontogenesis. However, until now little is known about the molecular mechanisms of the external genitalia development in goose. In the present study, comparative transcriptomic analyses were performed on the hypothalamus, pituitary gland, testis, and external genitalia isolated from the 245-day-old male Tianfu meat geese showing normal (NEGG, n = 3) and abnormal (AEGG, n = 3) external genitals in order to provide a better understanding of the mechanisms controlling the development of the external genitalia in aquatic bird species. RESULTS: There were 107, 284, 2192, and 1005 differentially expressed genes (DEGs) identified in the hypothalamus, pituitary gland, testis and external genitalia between NEGG and AEGG. Functional enrichment analysis indicated that the DEGs identified in the hypothalamus were mainly enriched in the ECM-receptor interaction pathway. The ECM-receptor interaction, focal adhesion, and neuroactive ligand-receptor interaction pathways were significantly enriched by the DEGs in the pituitary gland. In the testis, the DEGs were enriched in the neuroactive ligand-receptor interaction, cell cycle, oocyte meiosis, and purine metabolism. In the external genitalia, the DEGs were enriched in the metabolic, neuroactive ligand-receptor interaction, and WNT signaling pathways. Furthermore, through integrated analysis of protein-protein interaction (PPI) network and co-expression network, fifteen genes involved in the neuroactive ligand-receptor interaction and WNT signaling pathways were identified, including KNG1, LPAR2, LPAR3, NPY, PLCB1, AVPR1B, GHSR, GRM3, HTR5A, FSHB, FSHR, WNT11, WNT5A, WIF1, and WNT7B, which could play crucial roles in the development of goose external genitalia. CONCLUSIONS: This study is the first systematically comparing the hypothalamus, pituitary gland, testis, and external genitalia transcriptomes of male geese exhibiting normal and abnormal external genitals. Both bioinformatic analysis and validation experiments indicated that the neuroactive ligand-receptor interaction pathway could regulate the WNT signaling pathway through PLCB1 to control male goose external genitalia development.

Management of mammalian bites to the external genitalia: a scoping review.

OBJECTIVE: To review existing publications to determine the approaches for the medical and operative management of mammalian bites to the external genitalia. MATERIALS AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Review guidelines were followed. Four databases were searched. Articles were independently screened and analysed by two reviewers. Publications were included if detailed summaries of genitalia bites and management were documented. Discrepancies were resolved by a third reviewer. Data were extracted from the final article cohort. RESULTS: A total of 42 articles were included in this scoping review with 67 cases of mammalian bites to the genitalia reported in the cohort. The most common injury site was the penis (44.9%). Dog and human bites were the most common type of mammalian bites (61.2% and 26.9%, respectively). In all, 13.4% of cases were managed with medical therapy while 86.6% of cases required surgical intervention. The most common intervention was wound irrigation, debridement, and primary closure (32.8%). Although uncommon, other operative approaches included skin flaps (7.5%) and grafts (4.5%), re-implantation (4.5%), urethroplasty/repair (7.5%), penectomy (3.0%), scrotoplasty (3.0%), and perineal urethrostomy (1.5%). The reported complication rate was 19.4%. The mean follow-up time was 39.9 months. CONCLUSION: Trauma related to mammalian bites is associated with high utilisation of healthcare resources and cost. Although management of such bites to the genitalia is controversial, surgical intervention is often warranted ranging from simple debridement of devitalised tissue to complex reconstructive surgery. This review underscores the need for further investigation of mammalian bites to the genitalia to improve surgical options and monitor for long-term complication rates.

Estrogens and development of the mouse and human external genitalia.

The Jost hypothesis states that androgens are necessary for normal development of the male external genitalia. In this review, we explore the complementary hypothesis that estrogens can elicit abnormal development of male external genitalia. Herein, we review available data in both humans and mice on the deleterious effects of estrogen on external genitalia development, especially during the "window of susceptibility" to exogenous estrogens. The male and female developing external genitalia in both the human and mouse express ESR1 and ESR2, along with the androgen receptor (AR). Human clinical data suggests that exogenous estrogens can adversely affect normal penile and urethral development, resulting in hypospadias. Experimental mouse data also strongly supports the idea that exogenous estrogens cause penile and urethral defects. Despite key differences, estrogen-induced hypospadias in the mouse displays certain morphogenetic homologies to human hypospadias, including disruption of urethral fusion and preputial abnormalities. Timing of estrogenic exposure, or the "window of susceptibility," is an important consideration when examining malformations of the external genitalia in both humans and mice. In addition to a review of normal human and mouse external genital development, this article aims to review the present data on the role of estrogens in normal and abnormal development of the mouse and human internal and external genitalia. Based on the current literature for both species, we conclude that estrogen-dependent processes may play a role in abnormal genital development.

Ontogeny of estrogen receptors in human male and female fetal reproductive tracts.

This paper reviews and provides new observations on the ontogeny of estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) in developing human male and female internal and external genitalia. Included in this study are observations on the human fetal uterine tube, the uterotubal junction, uterus, cervix, vagina, penis and clitoris. We also summarize and report on the ontogeny of estrogen receptors in the human fetal prostate, prostatic urethra and epididymis. The ontogeny of ESR1 and ESR2, which spans from 8 to 21 weeks correlates well with the known "window of susceptibility" (7-15 weeks) for diethylstilbestrol (DES)-induced malformations of the human female reproductive tract as determined through examination of DES daughters exposed in utero to this potent estrogen. Our fairly complete mapping of the ontogeny of ESR1 and ESR2 in developing human male and female internal and external genitalia provides a mechanistic framework for further investigation of the role of estrogen in normal development and of abnormalities elicited by exogenous estrogens.

[Surgical complications in adult urology: Surgery of the external genitalia]. / Les complications chirurgicales en urologie adulte : chirurgie des organes génitaux externes.

AIM: Define and present the complications of surgery of the external genitalia (EG), as well as their management. METHOD: Bibliographic search using the Medline (NLM Pubmed tool) and Embase bibliographic databases using the following keywords: scrotal surgery, orchidopexy, hydrocele, varicocele, testicular biopsy, vasectomy, cryptorchidism, orchiectomy, testicular implant, subcapsular orchiectomy, spermatic cord cyst, posthectomy, penis curvature surgery, penile implant, urethral strictures. RESULTS: EG surgery is common in urology, it includes scrotal surgeries and penile surgeries, which are performed openly. They expose to complications such as bleeding, infection, scar disunity requiring early reassessment especially in case of ambulatory procedure. Rare complications must be known, some of which must lead to expert management. CONCLUSION: Complications of surgical treatment of EG should be identified and managed. This report should allow a better understanding and management of these complications.

Foxa1 and Foxa2 orchestrate development of the urethral tube and division of the embryonic cloaca through an autoregulatory loop with Shh.

Congenital anomalies of external genitalia affect approximately 1 in 125 live male births. Development of the genital tubercle, the precursor of the penis and clitoris, is regulated by the urethral plate epithelium, an endodermal signaling center. Signaling activity of the urethral plate is mediated by Sonic hedgehog (SHH), which coordinates outgrowth and patterning of the genital tubercle by controlling cell cycle kinetics and expression of downstream genes. The mechanisms that govern Shh transcription in urethral plate cells are largely unknown. Here we show that deletion of Foxa1 and Foxa2 results in persistent cloaca, an incomplete separation of urinary, genital, and anorectal tracts, and severe hypospadias, a failure of urethral tubulogenesis. Loss of Foxa2 and only one copy of Foxa1 results in urethral fistula, an additional opening of the penile urethra. Foxa1/a2 participate in an autoregulatory feedback loop with Shh, in which FOXA1 and FOXA2 positively regulate transcription of Shh in the urethra, and SHH feeds back to negatively regulate Foxa1 and Foxa2 expression. These findings reveal novel roles for Foxa genes in development of the urethral tube and in division of the embryonic cloaca.

Regulatory roles of epithelial-mesenchymal interaction (EMI) during early and androgen dependent external genitalia development.

Development of external genitalia (ExG) has been a topic of long mystery in the field of organogenesis research. Early stage male and female of mouse embryos develop a common genital tubercle (GT) in the perineum whose outgrowth extends distally from the posterior cloacal regions. Concomitant with GT outgrowth, the cloaca is divided into urogenital sinus and anorectum by urorectal septum (URS) internally. The outgrowth of the GT is associated with the formation of endodermal epithelial urethral plate (UP) attached to the ventral epidermis of the GT. Such a common developmental phase is observed until around embryonic day 15.5 (E15.5) morphologically in mouse embryogenesis. Various growth factor genes, such as Fibroblast growth factor (Fgf) and Wnt genes are expressed and function during GT formation. Since the discovery of key growth factor signals and several regulatory molecules, elucidation of their functions has been achieved utilizing mouse developmental models, conditional gene knockout mouse and in vitro culture. Analyses on the phenotypes of such mouse models have revealed that several growth factor families play fundamental roles in ExG organogenesis based on the epithelial-mesenchymal interaction (EMI). More recently, EMI between developing urethral epithelia and its bilateral mesenchyme of later stages is also reported during subsequent stage of androgen-dependent male-type urethral formation in the mouse embryo. Mafb, belonging to AP-1 family and a key androgen-responsive mesenchymal gene, is identified and starts to be expressed around E14.5 when masculinization of the urethra is initiated. Mesenchymal cell condensation and migration, which are regulated by nonmuscle myosin, are shown to be essential process for masculinization. Hence, studies on EMI at various embryonic stages are important not only for early but also for subsequent masculinization of the urethra. In this review, a dynamic mode of EMI for both early and late phases of ExG development is discussed.

[Male genital self-mutilation: A case series]. / Automutilation des organes génitaux externes chez l'homme.

INTRODUCTION: Genital self-mutilation is a rare phenomenon that often occurs on a psychotic ground. Its diagnosis is clinical and its management involves a coordinated action of urologists and psychiatrists. MATERIALS AND METHOD: We report a retrospective monocentric series of 14 cases of genital self-mutilation (penis and testicles), collected from January 2000 to May 2019. In addition to psychiatric care and according to the type of lesions, we performed implantations of penis, cutaneous urethrostomies, hemostatic ligature of spermatic cord, ablation of rings. The implantations of the penis were done without microscope or magnifying glass and on the basis only of an end-to-end anastomosis of the erectile bodies and the urethra. Sexual abstinence was indicated for 6weeks. RESULTS: The average age of our patients was 31.5years. We have identified ten cases of penis section including two incomplete, two cases of strangulation of penis by a metal ring, an isolated wound of the glans and three cases of testicular ablation, two of which were associated with a section of penis. We performed as first line: 5 penis reimplantation, 5 cutaneous urethrostomy, 2 ablation of strangulation rings and 3 hemostatic ligature of the spermatic cord. Three reimplanted patients had fairly satisfactory immediate operating suites: 2 patients healed well with good penile sensitivities, while one patient presented with a loss of penile skin sensitivity. The other two patients, on the other hand, presented on D1 a necrosis of the reimplanted stump, requiring an amputation and cutaneous urethrostomy. Also, necrosis of the strangulated penis was observed in one case and also required a second operating time with an amputation of the necrotic penis and a cutaneous urethrostomy. One patient died on D7 by autolysis. From a distance, the sexual and urinary function of reimplanted patients could not be assessed because they were lost to follow-up. Only a few patients who received a skin urethrostomy were seen at follow-up consultations. And with an average follow-up of 3years, no functional urinary disorder was found in them. CONCLUSION: The management of genital self-harm requires coordination between urologist and psychiatrist. With our conditions the results are mixed and penile reimplantation should ideally be done under a microscope with an experienced surgeon. However, it can be attempted as long as possible, with the possibility of making an urethrostomy in the second time in case of failure. The pillar of care for these patients, however, lies in a good psychiatric balance because they are not immune to recurrence or autolysis. LEVEL OF EVIDENCE: 3.

Contrasting mechanisms of penile urethral formation in mouse and human.

This paper addresses the developmental mechanisms of formation of the mouse and human penile urethra and the possibility that two disparate mechanisms are at play. It has been suggested that the entire penile urethra of the mouse forms via direct canalization of the endodermal urethral plate. While this mechanism surely accounts for development of the proximal portion of the mouse penile urethra, we suggest that the distal portion of the mouse penile urethra forms via a series of epithelial fusion events. Through review of the recent literature in combination with new data, it is unlikely that the entire mouse urethra is formed from the endodermal urethral plate due in part to the fact that from E14 onward the urethral plate is not present in the distal aspect of the genital tubercle. Formation of the distal portion of the mouse urethra receives substantial contribution from the preputial swellings that form the preputial-urethral groove and subsequently the preputial-urethral canal, the later of which is subdivided by a fusion event to form the distal portion of the mouse penile urethra. Examination of human penile development also reveals comparable dual morphogenetic mechanisms. However, in the case of human, direct canalization of the urethral plate occurs in the glans, while fusion events are involved in formation of the urethra within the penile shaft, a pattern exactly opposite to that of the mouse. The highest incidence of hypospadias in humans occurs at the junction of these two different developmental mechanisms. The relevance of the mouse as a model of human hypospadias is discussed.

Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial-Mesenchyme Interaction (EMI).

Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial-mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus constituting a form of paracrine signaling. The development of the urogenital organ, therefore, provides an intriguing opportunity to study EMI and its relationship with other pathways, such as hormonal signaling. Cellular interactions of prostate cancer (PCa) with its neighboring tissue is also noteworthy. The local microenvironment, including the bone metastatic site, can release cellular signals which can affect the malignant tumors, and vice versa. Thus, it is necessary to compare possible similarities and divergences in Hh signaling functions and its interaction with other local growth factors, such as BMP (bone morphogenetic protein) between organogenesis and tumorigenesis. Additionally, this review will discuss two pertinent research aspects of Hh signaling: (1) the potential signaling crosstalk between Hh and androgen signaling; and (2) the effect of signaling between the epithelia and the mesenchyme on the status of the basement membrane with extracellular matrix structures located on the epithelial-mesenchymal interface.

[Feminizing genitoplasty in virilization of the external genitalia].

The review focuses on the feminizing genitoplasty of the external genitalia in patients with disorders of sex development. The opinions of various surgeons and surgical schools on the timing, stages and methods of performing feminizing genitoplasty in girls with the virilization of the genitalia are presented. The development and improvement of surgical techniques for performing clitoroloplasty in patients with virilization of genitalia are described, as well as different types of labioplasty. The main methods of reconstruction of the urogenital sinus are given.