Penile Malformations Research Articles

Mouse hypospadias: A critical examination and definition

Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation. The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12–P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12–P10, DES P0–P10 and DES P5–P15 groups, and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12–P10, DES P0–P10 and DES P5–P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0–P10 period. In “estrogen mutant mice” (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process.

Pre-Pubic Phalloplasty by Abdominal Wall Z-Plasty for Epispadias Repair

Patients with bladder exstrophy-epispadias complex are known with several penile malformations. A 21-year old patient, with successful exstrophy-epispadias repair as a child, complained of a distinct, dorsal angulation of his penis in erection, making intercourse impossible. A pre-pubic abdominal wall Z-plasty was performed to widen the pre-pubic area with an excellent, functional result.

Isolated Male Epispadias: Anatomic Functional Restoration Is the Primary Goal.

Background. Isolated male epispadias (IME) is a rare congenital penile malformation, as often part of bladder-exstrophy-epispadias complex (BEEC). In its isolated presentation, it consists in a defect of the dorsal aspect of the penis, leaving the urethral plate open. Occurrence of urinary incontinence is related to the degree of dorsal displacement of the meatus and the underlying underdevelopment of the urethral sphincter. The technique for primary IME reconstruction, based on anatomic restoration of the urethra and bladder neck, is here illustrated. Patients and Methods. A retrospective database was created with patients who underwent primary IME repair between June 1998 and February 2014. Intraoperative variables, postoperative complications, and outcomes were assessed. A descriptive statistical analysis was performed. Results and Limitations. Eight patients underwent primary repair, with penopubic epispadias (PPE) in 3, penile epispadias (PE) in 2, and glandular epispadias (GE) in 3. Median age at surgery was 13.0 months [7–47]; median follow-up was 52 months [9–120]. Complications requiring further surgery were reported in two patients, while further esthetic surgeries were required in 4 patients. Conclusion. Anatomical restoration in primary IME is safe and effective, with acceptable results given the initial pathology.

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor α (ERα) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERα have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA.

Current understanding of hypospadias: relevance of animal models.

Hypospadias is a congenital abnormality of the penile urethra with an incidence of approximately 1:200-1:300 male births, which has doubled over the past three decades. The aetiology of the overwhelming majority of hypospadias remains unknown but appears to be a combination of genetic susceptibility and prenatal exposure to endocrine disruptors. Reliable animal models of hypospadias are required for better understanding of the mechanisms of normal penile urethral formation and hence hypospadias. Mice and/or rats are generally used for experimental modelling of hypospadias, however these do not fully reflect the human condition. To use these models successfully, researchers must understand the similarities and differences between mouse, rat and human penile anatomy as well as the normal morphogenetic mechanisms of penile development in these species. Despite some important differences, numerous features of animal and human hypospadias are shared: the prevalence of distal penile malformations; disruption of the urethral meatus; disruption of urethra-associated erectile bodies; and a common mechanism of impaired epithelial fusion events. Rat and mouse models of hypospadias are crucial to our understanding of hypospadias to ultimately reduce its incidence through better preventive strategies.

Les malformations congénitales du pénis

Congenital abnormalities of the penis are usually diagnosed at birth and pose aesthetic and functional problems sometimes requiring surgical management. A literature review was conducted on Medline considering the articles listed until January 2012. Hypospadias is the most common malformation (1 in 250 boys. Familial forms: 7%). The causes remain hypothetical but the doubling of the incidence in 30 years could be linked to fetal exposure to endocrine disruptors "estrogen-like" used in the food industry in particular. Surgical treatment is usually intended to improve the aesthetic appearance but sometimes, in case of significant curvature or posterior meatus, necessary for normal sexual life and fertility. Other malformations (epispades, buried penis, transpositions, twists and preputial abnormalities) as well as management for functional or aesthetic consequences of these malformations in adulthood require complex surgical care in a specialized environment. The improvement of surgical techniques and pediatric anesthesia allows an early and effective specialized surgical approach of penile malformations. Management of sequelae in adulthood must be discussed and requires experience of surgical techniques on pediatric and adult penis.

The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science

The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science

Simplified Surgical Approach to Congenital Megaprepuce: Fixing, Unfurling and Tailoring Revisited

Megaprepuce is a congenital penile malformation that includes phimosis and severe ballooning of the internal prepuce. We combined the main technical details of 2 previously reported surgical techniques to simplify the surgical approach. We report the key points of this revisited surgical correction for megaprepuce and the long-term results. Penile reconstruction was performed between March 2004 and March 2009 in 26 children 2 to 19 months old (median age 6) with congenital megaprepuce. Surgical repair consisted of limited preputial resection of the phimotic ring, wide dissection of the outer prepuce to the base of the penis, fixation of the proximal outer prepuce to Buck's fascia to create a new penoscrotal junction, and unfurling and wide tailoring of the inner prepuce in the ventral midline to resurface the whole elongated penile shaft. A bladder catheter was left in place for 5 or 6 days. Only patients with at least 6 months of followup were included in analysis. All patients underwent surgery on an outpatient basis. Operative time was between 50 and 85 minutes. Median followup was 17.6 months (range 6 to 59). Two patients had slight dehiscence of the ventral suture, which healed spontaneously without a scar. In 1 patient transient urethral meatal stenosis developed. The final cosmesis result was adequate in all patients. It is possible to correct megaprepuce and achieve an adequate genital aspect with a simple approach of resurfacing the penis with the unfurled, tailored inner prepuce.

Sexual Development and Fertility of Loxl1−/– Male Mice

Our objective was to investigate the genitourinary defects and fertility of the male lysyl oxidase-like 1 gene (Loxl1) knockout (Loxl1(-/-)) mouse, with particular attention to fecundity and testicular, epididymal, gubernacular, and penile histopathology, which may lead us to a better understanding of the role of the elastin-homeostasis gene, LOXL1, in male sexual development. Genital morphometric evaluation of 6- to 9-month-old male Loxl1(-/-) mice (n = 26) was compared with C57Bl/6 controls (n = 24). Measurements included: body weight, scrotal development, evidence of feminization (nipples or vaginal pouch), penile malformations, anogenital distance, and absence/presence and size of perineal bulge. Sperm production was estimated using a standardized technique. A breeding program was conducted to determine how much of the infertility observed in Loxl1(-/-) pairs was due to the male factor. Finally, we performed histopathologic comparison of the genitourinary organs of Loxl1(-/-) and control mice. Loxl1(-/-) mice weighed less than their age-matched C57Bl/6 counterparts (P < .001). Size-adjusted perineal bulge was larger (P < .001), and resting location of the gonads was higher intra-abdominally (P = .048) in the Loxl1(-/-) mice. Estimates of daily sperm counts revealed that the Loxl1(-/-) mice had lower sperm production (P = .048). Loxl1(-/-) males bred with control females demonstrated relative fecundity values intermediate between Loxl1(-/-) pairs (lowest fecundity) and control pairs (highest fecundity), suggesting a component of male-factor infertility. No histologic differences were noted using hematoxylin-eosin or specialized elastin staining of the gonads, gubernaculum, and penis. Although further studies are warranted, these findings suggest a subtle and likely multifactorial role of the LOXL1 protein in male sexual development and fertility.

Outcome after repair of congenital penile malformations.

Penile malformations seen and treated during childhood may result in voiding disorders and sexual malfunction in adults. Preputial synechia and phimosis will seldom be the reason for these problems, although some men do seek treatment to correct radical circumcision. Little is known about the satisfaction of men with neonatal or childhood circumcision. Congenital penile curvature is seen in 0.4-0.6% of men. Slight bends do not need any operative treatment and young men should be given advice and counselling accordingly. If treatment is needed, a standard Nesbit procedure or one of its modifications is used in order to avoid urethral manipulation. A hypospadiac position of the urethral meatus together with a more or less prominent ventral bending of the penis is seen in another 0.3-0.5% of boys. Reports on more than 200 operations to correct this deformity have been published. Between 5 and 25% of early complications such as fistula formation, stenosis of the neourethra and skin problems result from hypospadias repair. Long-term follow-up studies have shown that adulthood satisfaction with respect to voiding and sexual function is achieved in 2/3 and some degree of dissatisfaction in 1/3 of cases. Epispadias repair is a much more complicated procedure and long-term results are seldom reported. Nevertheless, quite good results with respect to continence (approximately 80%) and sexual function may be achieved.

HYPOSPADIAS REPAIR

Place of Study: The Departments of Urology, Paediatric Surgery and Plastic Surgery, Quaid-e-AzamMedical College, Bahawal Victoria Hospital, Bahawalpur. Duration of Study: Jan 1999 to Dec 2004. Design of Study:Prospective. Materials&amp;Methods: Patients admitted with hypospadias in these departments were included in this studyexcept patients with multiple failed repairs previously. Standard procedures were practiced for every type of defect i.e.MAGPI and Mathieu’s repair for coronal hypospadias, Snodgrass urethroplasty for proximal and distal penilehypospadias. Results: The age range observed during this study was 1.5 to 25 years while 64% of patients were lessthan 10 years of age. The type of defect was coronal in 25%, penile in 60%, penoscrotal and perineal in 15% of thepatients. Initial success rate was 78% and overall success rate was 92%. Complications observed were fistulaformation 7% , stenosis of anastomotic site 7% and dehiscence of repair 3%. Conclusion: Thorough evaluation ofurethral and penile malformation brings best outcome of surgery for hypospadias. Hypospadias repair should be offeredto the child before school going age so as to prevent psychological impacts of genital malformations.

Esthetic Outcomes of Genitoplasty in Males Born With Bladder Exstrophy and Epispadias

Male children born with bladder exstrophy-epispadias complex may have poor self-image because the esthetic aspects of the genitalia acquire greater significance with age. We reviewed our long-term outcomes of genitoplasty in males born with exstrophy-epispadias complex with emphasis on the esthetic results. A total of 70 male patients with exstrophy-epispadias complex were the basis of this retrospective review. Primary and secondary genitoplasty was performed in 44 and 26 patients, respectively. Various surgical methods were implemented for genitoplasty, including Cantwell Ransley technique with or without paraexstrophy flaps in 36 cases, partial corporeal mobilization with or without dermal graft in 16, subperiosteal corporeal mobilization from the pubic rami in 7 and complete penile disassembly in 6. The parent and when appropriate the patient determined satisfaction with the cosmetic appearance. The incidence of postoperative complications and need for surgical revision were noted. Long-term followup was available in 65 of 70 patients. Esthetic satisfaction was present in 60 of 65 patients (92%). A total of 19 revisions (29%) were required with 4 patients undergoing multiple revisions. These revisions included fistula repair, repair of urethral stricture, glanular contouring and recurrent chordee release. The penile malformations observed in exstrophy-epispadias complex may be due to a short urethral strip, corporeal disproportion and/or iatrogenic scarring. The optimal method to correct corporeal disproportion includes placement of a dermal graft. In select cases careful and partial mobilization of the crura from the pubic rami allows penile lengthening. In secondary reconstructive efforts subperiosteal dissection provides a virgin surgical field, while protecting neurovascular and erectile structures.

Late Gestational Exposure to the Fungicide Prochloraz Delays the Onset of Parturition and Causes Reproductive Malformations in Male but Not Female Rat Offspring1

Prochloraz (PZ) is an imidazole fungicide that displays multiple endocrine activities. It inhibits steroid synthesis via P450 modulation and acts as an androgen receptor (AR) antagonist, but its effects on male sexual differentiation have not been described. The purpose of the current study was to expand in vitro observations and to determine whether PZ affected sexual differentiation. PZ effects on AR-mediated gene expression were tested using a cell line (MDA-kb2) containing endogenous AR and stably transfected with an MMTV-luc reporter. PZ concentrations greater than 1 microM caused a dose-dependent inhibition of dihydrotestosterone-induced gene expression. PZ also inhibited R1881 binding to the rat AR (IC50 approximately 60 microM). In vivo, pregnant rats received PZ by gavage from Gestational Day 14 to 18 at doses of 31.25, 62.5, 125, and 250 mg/kg of body weight per day. PZ delayed delivery in a dose-dependent manner and resulted in pup mortalities at the two highest doses. In male offspring, anogenital distance and body weight were slightly reduced at 3 days of age. Additionally, female-like areolas were observed at 13 days of age at frequencies of 31%, 43%, 41%, and 71% in the lowest-dose to highest-dose groups, respectively. Weights of androgen-dependent tissues showed dose-dependent reductions. Hypospadias and vaginal pouches were noted in all males treated with 250 mg/kg, whereas those defects were observed in 12.5% and 6.25%, respectively, of males treated with 125 mg/kg. Treatment did not affect age of preputial separation in animals without penile malformations. Despite severe malformations in males, no malformations were noted in females. Together, these results indicate that PZ alters sexual differentiation in an antiandrogenic manner.

Abnormalities of Sexual Development in Male Rats with in Utero and Lactational Exposure to the Antiandrogenic Plasticizer Di(2-Ethylhexyl) Phthalate

Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP), on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens.

Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate.

Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP), on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens.

Use of Dermal Graft and Free Urethral Graft in Penile Reconstruction

From 1979 to 1987 we treated 28 patients with severe penile malformations who required a dermal graft to straighten the shaft and a free graft to construct a urethra. In 10 patients the 2 grafts were placed simultaneously with good results. In 15 patients the dermal graft was placed initially and a urethral graft was placed over it later. In 3 patients the urethroplasty has not been done yet. No complications resulted from the combined use of dermal and urethral free grafts. The principle of 舠graft on graft舡 can be applied successfully to correct certain severe penile problems. Indications, technique and results are presented.

Penile malformation, gender identity and sexual orientation.

Gender identity and sexual orientation were investigated in 34 men operated for hypospadias in childhood and in 36 matched control subjects. Independent psychiatric assessments from semi-structured interviews, and double-blind formalized psychological ratings from the Rorschach, yielded similar findings. The probands were less secure in their maleness but were similar in sexual orientation as compared to the controls. A third blind, independent measure of unconscious gender identity, the Franck Drawing Completion Test, gave further evidence of uncertain gender identity in the patients. A self-administered inventory, the Gough Femininity Scale, showed a tendency for the patients to take more feminine sex roles. The findings are discussed from psychoendocrinological as well as psycho-analytical view points. The need for early psychological preventive measures for hypospadic boys and their parents is stressed.

Penile malformation and mental health. A controlled psychiatric study of men operated for hypospadias in childhood.

Aspects of mental health were investigated by means of interviews and register data in 34 men operated on for hypospadias in childhood and in 36 matched control subjects. Most hypospadiacs adjust well both in childhood and adult age. However, they reported more neurotic disturbances in their childhood than the controls. Shyness and enuresis were common troubles among the probands, and they had been more timid, isolated and mobbed. Similar although less striking differences in mental health were reported also in adult age. Depression and anxiety were dominating symptoms. The interviewer assessed the hypospadiacs to show more anxiety and to use more immature defence mechanisms and consequently to have less stress tolerance. The probands were further judged to have less capacity for social relations and their overall capacity to utilize existent psychological resources was small as compared to the controls. The findings indicate that hypospadiacs are more prone to neurotic (but not psychotic) disturbances than other young men and have more disturbed social relations. The need for psychological guidance for the boys and their parents is stressed.

Unusual case of urethral duplication

We present a case of unique penile malformation, a child with common prostatic urethra with two normal, double urethras parallel to one another with a bifid glans penis. This case emphasizes how abnormal embryology can contribute to our knowledge of normal development.

THE CORRECTION OF HYPOSPADIAS

A thorough evaluation of both urethral and penile malformation are mandatory for the choice of the best surgical treatment of patients with hypospadias. The site and the size of the urethral meatus, the presence of a chordee and of a velamentous distal urethra must be carefully assessed. In distal (glandular and coronal) hypospadias, the meatal advancement with glanduloplasty is the treatment of choice. In proximal hypospadias with chordee, the transverse preputial island flap according to the Duckett's technique allows a one-stage hypospadias repair. The awareness of the possible psychologic impact of genital malformations in childhood recommends an early correction of hypospadias, if possible during the first year of life.