Cause Of Hypospadias Research Articles

No association between maternal pre-pregnancy obesity and risk of hypospadias or cryptorchidism in male newborns

Hypospadias and cryptorchidism, two relatively common male genital anomalies, may be caused by altered maternal hormone levels, blood glucose levels, or nutritional deficiencies. Maternal obesity, which increases risk of diabetes and could influence hormone levels, may, therefore, be associated with risk of hypospadias and cryptorchidism. The purpose of this study was to assess the association between pre-pregnancy maternal obesity and hypospadias and cryptorchidism. We conducted a case-control study of hypospadias and cryptorchidism in male singleton newborns using Washington State birth records from 1992 to 2008 linked to birth-hospitalization discharge records. Maternal pre-pregnancy body mass index (BMI) was calculated from pre-pregnancy weight and height. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for hypospadias or cryptorchidism were estimated by fitting multivariable logistic regression models adjusted for year of birth, and maternal age, education, parity, race, and cigarette smoking during pregnancy. The complete-case analysis included 2219 hypospadias cases, 2563 cryptorchidism cases, and 32,734 controls. Maternal obesity (BMI ≥30 kg/m(2) ) was not associated with risk of hypospadias or cryptorchidism in male offspring: hypospadias (aOR, 1.07; 95% CI, 0.95-1.21); cryptorchidism (aOR, 0.99; 95% CI, 0.89-1.11), and no trend in risk with increasing maternal BMI was found. There was little indication of risk associated with BMI among any subgroup of mothers examined, including women with pre-existing diabetes or hypertension, women who developed preeclampsia, non-Hispanic white women, first-time mothers, or mothers aged ≥30 years. The results of this study do not support the hypothesis that pre-pregnancy maternal obesity is a cause of hypospadias or cryptorchidism in male infants.

Is Activating Transcription Factor 3 Up-Regulated in Patients with Hypospadias?

PurposeEven though hypospadias is one of the most common congenital anomalies, the cause of hypospadias is largely unknown. With regard to molecular biology and microarray technology, it appears that hypospadias is potentially related to disrupted gene expression. Genomic analysis of hypospadiac tissue indicated a potential role for activating transcription factor 3 (ATF3) in the development of this anomaly. This study prospectively examined the expression of ATF3 in tissues from 20 children with hypospadias compared with 26 normal penile skin tissue samples from elective circumcision.Materials and MethodsPrepucial tissue was obtained from children who underwent repair of hypospadias for comparison with tissue samples from children who underwent elective circumcision. Skin specimens were evaluated for the expression of ATF3 protein by immunohistochemical staining.ResultsImmunohistochemical staining for ATF3 in samples from children who underwent repair of hypospadias was significantly greater than in samples from children who underwent elective circumcision (80% vs. 11%, respectively; p<0.05).ConclusionsOur results indicate that ATF3 is up-regulated in the penile skin tissue of boys with hypospadias, which suggests a role for this transcription factor in the development of this abnormality.

Clinical Dilemmas and Surgical Treatment of Penoscrotal, Scrotal and Perineal Hypospadias

Hypospadia is the most common congenital malformation of the urinary tract. It is a malformation with the opening of the urethra proximally from the usual site. The meatal opening can be anywhere alone the shaft of the penis, or in more severe forms, within the scrotum, or in the perineum. Consequently the hypospadias can be distal, medial and proximal. The proximal ones can be penoscrotal (PS), scrotal (SC) and perineal (PE). The cause of hypospadias is largely unknown; however, current epidemiology and laboratory studies have shed new light into the etiology of hypospadias. With recent advancements in molecular biology, microarray technology, it appears that hypospadias is potentially related to disrupted gene expression. Currently, the only available treatment is surgery. The aim of this study was to present our results of the surgical correction of hypospadias and methods used to answer the clinical dilemmas about the gender. Authors have used two methods for a surgical resolution of the hypospadia - one-step operation suggested by Snodgrass and two-step operation, employing free graft suggested by Bracka. Clinical dilemmas regarding the gender were answered using cytogenetic assessment through lymphocyte cultivation method, suggested by Seabright. The cytogenetic assessment was carried in 23 patients with proximal hypospadia (penoscrotal, scrotal and perineal). Characteristic male cariotype (46, XY) was found in 22 patients. In one patient, with scrotal hypospadia, we found the characteristic female cariotype. This patient had testicles. The patient with female cariotype had a TDG gene that determines the differentiation of the testicles. Although surgery remains the only therapy for the treatment of the hypospadias, better understanding of the molecular and hormonal mechanisms behind the diseases may contribute to the prevention and the decrease in the incidence of the malformation. Cytogenetic testing in patients with unclear gender is important in planning further treatment.

Endocrine Disruptors, Genital Development, and Hypospadias

Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 125 live male births. Embryological studies have demonstrated that, depending on where the urethral development arrests, the meatal opening can be anywhere along the shaft of the penis or, in more severe forms, within the scrotum or in the perineum. Currently, the only available treatment is surgery. If left uncorrected, especially in its severe form, there is risk of infertility and psychological effects, such as avoidance of intimate relationships. The cause of hypospadias is largely unknown; however, current epidemiology and laboratory studies have shed new light into the etiology of hypospadias. With recent advancements in molecular biology and microarray technology, it appears that hypospadias is potentially related to disrupted gene expression. Specifically, some of the environmental chemicals are acting as antiandrogens and interfere directly with the action of testosterone-related gene expression. In this paper, we briefly review the normal development of male external genitalia and the prevalence and environmental risk factors related to hypospadias. In addition, we discuss some of the recent laboratory findings that contribute to our current understanding of this disease.

Quantitative Measurement of the Androgen Receptor in Prepuces of Boys with and Without Hypospadias

PURPOSE Identifiable causes of hypospadias, a midline fusion defect of the male ventral urethra, are still infrequently well-known. The aim of this study was to quantify the androgen receptor mRNA and androgen receptor protein in prepuces of boys with and without hypospadias. MATERIAL AND METHODS Forty prepuce specimens of circumcised boys, aged between 12 and 14 months, with (n=20) and without hypospadias (n=20), were investigated. Immediately after surgery all probes were fixed in formaldehyde and small parts were deep frozen in liquid nitrogen at -80° C. The total RNA of the specimens was isolated and cDNA was written. With the aid of real time PCR the amount of present androgen receptor mRNA was measured. For quantification of present androgen receptor protein, Western Blot (Bradford method) and immunohistochemistry for androgen receptor using standardized automated procedures (Discovery XT, Ventana) were performed. Statistical analyses using the the Kolmogorov-Smirnov and Mann-Whitney U-test were done. RESULTS Our observations show that the androgen receptor mRNA is significantly increased in the prepuce of hypospadiac boys compared to specimens of boys with phimosis.(p<0,01) similarly the amount of androgen receptor protein is increased compared to healthy boys. (p<0.01) Our results provide evidence that the rise of androgen receptor mRNA and protein seems to be an indirect expression of a decreased androgen receptor DNA binding capability possibly indicating further missing polypeptide encoding. CONCLUSIONS Our results provide evidence that the different expression of androgen receptor mRNA indicates the extent of a defect androgen receptor signalling in boys with hypospadias.

Hypospadias in a Male Patient with 21-hydroxylase Deficiency

A 17-day-old Japanese boy was transferred to the hospital because of vomiting and impaired consciousness. His external genitalia was pigmented associated with small penis and penoscrotal hypospadias. He was diagnosed as suffering from adrenal deficiency according to severe electrolyte abnormality, moderate hypoglycemia, metabolic acidosis and extremely elevated 17-OHP and testosterone levels. He turned out to be a compound heterozygote of CYP21A2 mutations by genetic analysis. Through endocrinological evaluation, he seemed to have normal hypophyseal function, intact testosterone production and appropriate 5-alpha-reductase-2 activity. Partial androgen insensitivity could not be ruled out by slight decrease of SHBG in hCG loading test, although mutation was not detected on androgen receptor gene. This is a rare case of a male patient with 21-hydroxylase deficiency accompanied by hypospadias. As the cause of hypospadias in this case has yet to be elucidated, further investigation and careful follow-up are required.

Consultation with the specialist: hypospadias.

1. Warren T. Snodgrass, MD* 1. *Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX After completing this article, readers should be able to: 1. Describe the incidence and cause of hypospadias. 2. Determine when evaluation for intersexuality should be considered in a child who has hypospadias. 3. Delineate when boys who have hypospadias should undergo surgical correction. A term baby is found on initial newborn examination to have penoscrotal hypospadias. The family is distressed and asks several questions: 1. Does he have any other problems, and is this an intersex condition? 2. Does he need other tests? 3. Can he urinate the way he is? 4. Why did this happen, and since we never heard of it before, how common is it? 5. Can it be fixed, and if so, when? Who should do the surgery? 6. We planned to have you circumcise him; can you still do that? Hypospadias refers to incomplete urethral development that results in a meatus located anywhere from the proximal glans to the perineum. The condition occurs in approximately 1 in 150 to 1 in 300 males, making hypospadias the second most common birth defect in boys after cryptorchidism. Recent surveys suggest that the incidence of hypospadias is increasing in industrialized countries, possibly due to environmental estrogens or antiandrogens. The external genitalia are initially indifferent and, in the absence of androgen, inherently develop the female phenotype. The critical timeframe for phallic development is from 8 to 12 weeks’ gestation, when the genital tubercle elongates and the urethral plate on its ventral surface tubularizes from proximally to the tip of the glans. During this phase, the penis is curved ventrally because the corpora cavernosa, as well as shaft skin and prepuce, develop faster on the dorsal than the ventral aspect. After 12 weeks’ gestation, androgen stimulation increases the size of the phallus. Hypospadias results from an arrest in these normal processes. The incompletely tubularized urethra opens on the undersurface, …

Development of the penile urethra.

In humans hypospadias consists of an abnormal ventral urethral meatus, incomplete formation of the prepuce and penile curvature (Baskin et al., 1998). The cause of hypospadias is thought to be failure of formation or fusion of the urethral folds bounding the urethral groove. While failure of urethral fold fusion may be the ultimate cause of hypospadias, there are many other possible causes of this malformation. In this review, the development of the penile urethra will be described for both the human and the mouse. The purpose of this paper is to review the developmental anatomy of the external genitalia to provide a framework for subsequent chapters that will focus on mechanisms of penile development. The second goal of this review is to discuss the development of the external genitalia of the human and the mouse so as to evaluate the mouse as a relevant animal model for development of the external genitalia.

ETIOLOGICAL STUDIES OF SEVERE OR FAMILIAL HYPOSPADIAS

Hypospadias is a congenital anomaly occurring in 1250 to 1830 live male births, of which 20% involve a severe type. The recurrence risk in families is high. In the majority of cases the underlying etiology remains unknown, which hampers further management based on the specific requirements associated with a specific etiology. In a single center study 63 unselected cases of severe hypospadias were studied for all presently known causes of hypospadias using clinical as well as molecular biological techniques. Also, 16 families with hypospadias were analyzed for possible androgen receptor gene mutations. In 31% of cases of severe hypospadias the underlying etiology was identified. Of these 31% of cases 17% were due to complex genetic syndromes, 9.5% were due to chromosomal anomalies, and 1 involved the vanishing testes syndrome, the androgen insensitivity syndrome and 5alpha-reductase type 2 deficiency, respectively. Based on hormone stimulation tests Leydig cell hypoplasia and disorders of testosterone biosynthesis were suspected in some patients but not confirmed by mutation analysis of the respective genes. Familial hypospadias was due to androgen insensitivity in only 1 family but no other etiologies were identified in this group. Using patient history, physical examination, karyotyping, hormonal evaluation, including human chorionic gonadotropin testing in prepubertal cases and additional biochemical and molecular genetic evaluation, an etiological diagnosis was made in 31% of cases of severe hypospadias. This diagnosis has implications for further patient treatment. In addition, familial hypospadias is rarely due to the androgen insensitivity syndrome.

Androgen Receptor Gene Mutations are Rarely Associated with Isolated Penile Hypospadias

Purpose Hypospadias has no known single etiology but it has been linked to androgen insensitivity caused by mutations of the androgen receptor gene. The purpose of this study was to search for such mutations in cases of various degrees of isolated hypospadias to determine whether such an association exists and, if so, with any particular anatomical subgroup. Materials and Methods Isolated deoxyribonucleic acid from the penile tissue of 40 patients undergoing reconstructive surgery was screened for mutations of the coding regions of the androgen receptor gene using single strand conformational polymorphism analysis. In cases with abnormal single strand conformational polymorphism findings sequence analysis of the deoxyribonucleic acid was performed to define the mutation. Results A missense mutation of exon 2 of the androgen receptor gene was noted in 1 patient with isolated distal penile shaft hypospadias. Sequence analysis revealed that the mutation changed amino acid residue 546 from proline to serine. No abnormalities were detected in the other 39 patients. Conclusions Isolated distal shaft hypospadias is associated with mutations of the androgen receptor gene but these mutations appear to be a rare cause of hypospadias.

Androgen Receptor Gene Mutations are Rarely Associated with Isolated Penile Hypospadias

Hypospadias has no known single etiology but it has been linked to androgen insensitivity caused by mutations of the androgen receptor gene. The purpose of this study was to search for such mutations in cases of various degrees of isolated hypospadias to determine whether such an association exists and, if so, with any particular anatomical subgroup. Isolated deoxyribonucleic acid from the penile tissue of 40 patients undergoing reconstructive surgery was screened for mutations of the coding regions of the androgen receptor gene using single strand conformational polymorphism analysis. In cases with abnormal single strand conformational polymorphism findings sequence analysis of the deoxyribonucleic acid was performed to define the mutation. A missense mutation of exon 2 of the androgen receptor gene was noted in 1 patient with isolated distal penile shaft hypospadias. Sequence analysis revealed that the mutation changed amino acid residue 546 from proline to serine. No abnormalities were detected in the other 39 patients. Isolated distal shaft hypospadias is associated with mutations of the androgen receptor gene but these mutations appear to be a rare cause of hypospadias.

Effect of Parenteral Testosterone Therapy on Penile Development in Boys with Hypospadias

Forty boys with hypospadias received 2 mg/kg testosterone esters intramuscularly 5 and 2 weeks before surgical correction of the hypospadias. The effects on penile development were determined 3 and 5 weeks after the first injection and 3 and 12 months post-operatively. A significant effect on penile development was shown. This effect disappeared during the first year following treatment. There was no effect on bone maturation, children's height and the ultimate testosterone level. All adverse effects disappeared after cessation of therapy. Androgen receptor deficiency as a possible cause of hypospadias is not supported by our observations.

Hypospadias.

Hypospadias results in various degrees of deficiency of the urethra, corpus spongiosum, and corpora cavernosa. The fibrous tissue that causes ventral curvature replaces Buck fascia and dartos fascia. The skin on the ventral surface may be thin; the prepuce is deficient ventrally and forms a dorsal hood over the glans.As a rule, the location of the meatus does not cause significant obstructive urinary symptoms, although ventral deflection of the stream of urine commonly occurs. When the meatus is more proximal, the stream flows straight downward or backward, requiring the patients to urinate ad modum feminarum. Uncorrected, the curvature of the penis is likely to cause painful erections and result in severe psychologic consequences.INCIDENCE/GENETICSThe incidence of hypospadias is about 1 in every 300 male children. If minor degrees of hypospadias are included, this incidence may be as high as 1 in 125 male births. If 1 848 500 male births occur in the United States, we should see 6200 hypospadias cases each year.The risk of occurrence in an infant is 8% if his father has hypospadias and 14% if a sibling has the condition; if two members of the same family have hypospadias, the risk is about 21%.The cause of hypospadias is still unknown.

Hypospadias

Hypospadias results in various degrees of deficiency of the urethra, corpus spongiosum, and corpora cavernosa. The fibrous tissue that causes ventral curvature replaces Buck fascia and dartos fascia. The skin on the ventral surface may be thin; the prepuce is deficient ventrally and forms a dorsal hood over the glans. As a rule, the location of the meatus does not cause significant obstructive urinary symptoms, although ventral deflection of the stream of urine commonly occurs. When the meatus is more proximal, the stream flows straight downward or backward, requiring the patients to urinate ad modum feminarum. Uncorrected, the curvature of the penis is likely to cause painful erections and result in severe psychologic consequences. INCIDENCE/GENETICS The incidence of hypospadias is about 1 in every 300 male children. If minor degrees of hypospadias are included, this incidence may be as high as 1 in 125 male births. If 1 848 500 male births occur in the United States, we should see 6200 hypospadias cases each year. The risk of occurrence in an infant is 8% if his father has hypospadias and 14% if a sibling has the condition; if two members of the same family have hypospadias, the risk is about 21%. The cause of hypospadias is still unknown.

Androgen Receptor Levels and 5α-Reductase Activities in Preputial Skin and Chordee Tissue of Boys with Isolated Hypospadias

The cause of hypospadias in the majority of patients is unknown. We examined the hypothesis that hypospadias might be explained by androgen receptor abnormalities in the atretic spongiosal tissue commonly known as chordee. We studied 10 patients with relatively severe hypospadias but with a predominantly male phenotype and no readily ascertained explanation for the defect, including no evidence of an abnormality in testosterone biosynthesis. Eight subjects had midshaft hypospadias and 2 had a penoscrotal meatus. All 10 patients had severe chordee. Serum concentrations of testosterone, and luteinizing and follicle-stimulating hormones were measured before human chorionic gonadotropin stimulation and a serum testosterone level was determined 24 hours after the last dose of a 5-day human chorionic gonadotropin stimulation (3,000 units per M.2 per day).Androgen receptor content and binding affinity were assayed in fibroblasts cultured from preputial skin and chordee tissue of patients and foreskin from normal male neonates. With the endogenous ligand dihydrotestosterone the mean number (maximum binding capacity) of androgen receptors was 1,013 fmol. per mg. deoxyribonucleic acid in preputial skin and 833 fmol. per mg. deoxyribonucleic acid in chordee tissue of patients, and 627 fmol. per mg. deoxyribonucleic acid in the foreskin of controls. With the nonmetabolizable, synthetic androgen methyltrienolone (R1881) the mean maximum binding capacity was 1,004, 722 and 758 fmol. per mg. deoxyribonucleic acid, respectively. Dihydrotestosterone receptor affinity (dissociation constant) was similar in preputial skin (0.20nM.) and chordee tissue (0.21nM.) from patients, and foreskin (0.29nM.) from controls. Androgen receptor binding affinity of R1881 also was similar (0.30, 0.24 and 0.21nM., respectively). Furthermore, the 5 α-reductase activity of preputial skin and chordee tissue of patients with hypospadias was similar to that of foreskin from normal neonates.In conclusion, isolated hypospadias in these subjects was not associated with androgen insensitivity of the spongiosal tissues on the basis of either decreased androgen receptor binding affinity, receptor number or conversion of testosterone to dihydrotestosterone.

On aetiological factors in hypospadias.

An analysis of genetic and non-genetic factors which might be of importance for the aetiology of hypospadias was performed in a clinical and in a registered material comprising altogether 893 hypospadiacs. Of 213 index patients in the clinical material, the probable aetiology was known in 11: in 3 patients chromosomal aberrations, in 2 well-defined syndromes with a known genetic background, in one maternal diabetes, in 2 maternal rubella, and 2 of the hypospadiacs were born after the mothers' use of anticonvulsant drugs and one after the mother's use of thalidomide. Other hypospadiacs were identified in 28 of the families of the remaining 202 index patients. As regards inheritance, 10 cases of hypospadias associated with clinodactyly were found in one family and this suggests an autosomal dominant gene as the cause of hypospadias. In the great majority (174/213) of index patients neither genetic nor non-genetic factors could be demonstrated but a significant cyclic trend for the month of birth and the month of the last menstrual period was found.