Hypospadias

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Overview
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urethral meatus (opening). Instead of opening at the tip of the glans of the penis, a hypospadic urethra opens anywhere along a line (the urethral groove) running from the tip along the underside (ventral aspect) of the shaft to the junction of the penis and scrotum or perineum. A distal hypospadias may be suspected even in an uncircumcised boy from an abnormally formed foreskin and downward tilt of the glans.

The urethral meatus opens on the glans penis in about 50-75% of cases; these are categorized as first degree hypospadias. Second degree (when the urethra opens on the shaft), and third degree (when the urethra opens on the perineum) occur in up to 20 and 30% of cases respectively. The more severe degrees are more likely to be associated with chordee, in which the phallus is incompletely separated from the perineum or is still tethered downwards by connective tissue, or with undescended testes (cryptorchidism).

Incidence
Hypospadias are among the most common birth defects of the male genitalia (second to cryptorchidism), but widely varying incidences have been reported from different countries, from as low as 1 in 4000 to as high as 1 in 125 boys.

There has been some evidence that the incidence of hypospadias around the world has been increasing in recent decades. In the United States, two surveillance studies reported that the incidence had increased from about 1 in 500 total births (1 in 250 boys) in the 1970s to 1 in 250 total births (1 in 125 boys) in the 1990s. Although a slight worldwide increase in hypospadias was reported in the 1980s, studies in different countries and regions have yielded conflicting results and some registries have reported decreases.

Causes
Most hypospadias are sporadic, without inheritance or family recurrence. For most cases, no cause can be identified though a number of hypotheses related to inadequate androgen effect, or environmental agents interfering with androgen effect, have been offered. Among the suspected environmental agents have been various chemicals, sometimes termed endocrine disruptors, that interact with steroid receptors. Putative endocrine disruptors include phthalates, DDT, and PCB. A recent questionnaire study of mothers who bore infants with hypospadias reported fivefold higher risk association with vegetarian diet (with plant phytoestrogens the hypothetical link) during pregnancy, and weaker associations with iron supplementation or influenza during early pregnancy. The associations are as yet uncorroborated by additional surveys or other methods.

Prenatal testosterone, converted in the genital skin to dihydrotestosterone, causes migration of skin fibroblasts to fully enclose the urethral groove in fetal males, normally resulting in an enclosed penile urethra by the second trimester of pregnancy. Failure of adequate prenatal androgen effect is therefore thought to be involved in many cases, making hypospadias a very mild form of intersex (undervirilization of a genetic male). Since postnatal androgen deficiency can only be demonstrated in a minority of cases, it has been proposed that transient deficiency of testosterone can occur during critical periods of fetal genital development, due to elevation of anti-müllerian hormone or more subtle degrees of pituitary-gonadal dysfunction. More recently, abnormalities of transcription factors have been proposed.

In animals, several teratogenic drugs or chemicals can cause hypospadias by interfering with androgen action in the embryo. Speculation that environmental agents-- endocrine disruptors-- might be interfering with human hormone systems has not been proven. The agents that have caused hypospadias in a small number of boys have been maternal use of synthetic progestins and finasteride in the first two trimesters of pregnancy. In 2002, it was suggested that maternal use of diethylstilbestrol, a synthetic estrogen, resulted in a 20-fold increase in prevalence of hypospadias although a followup study showed the risk, though present, to be much lesser.

In a minority of cases a postnatal deficiency of, or reduced sensitivity to, androgens (testosterone and dihydrotestosterone) can be demonstrated. These are often associated with a chordee, and in severe cases a residual perineal urogenital opening and small phallus. This combination of birth defects is referred to as pseudovaginal perineoscrotal hypospadias and is part of the spectrum of ambiguous genitalia. Treatment with testosterone postnatally does not close the urethra.

Genetic factors are likely involved in at least some cases, as there is about a 7% familial recurrence risk.

Rare iatrogenic urethral injuries similar to hypospadias after procedures such as surgery, catheterization, or circumcision have been reported.



Treatment
First degree hypospadias are primarily a cosmetic defect and have little effect on function except for direction of the urinary stream. If uncorrected, a second or third degree hypospadias can make male urination messy, necessitate that it be performed sitting, impair delivery of semen into the vagina (possibly creating problems with fertility), or interfere with erections. In developed countries, most hypospadias are surgically repaired in infancy. Surgical repair of first and second degree hypospadias is nearly always successful in one procedure, usually performed in the first year of life by a pediatric urologist or a plastic surgeon.

When the hypospadias is third degree, or there are associated birth defects such as chordee or cryptorchidism, the best management can be a more complicated decision. A karyotype and endocrine evaluation should be performed to detect intersex conditions or hormone deficiencies. If the penis is small, testosterone or human chorionic gonadotropin (hCG) injections may be given to enlarge it prior to surgery.

Surgical repair of severe hypospadias may require multiple procedures and mucosal grafting. Preputial skin is often used for grafting and circumcision should be avoided prior to repair. In a minority of patients with severe hypospadias surgery produces unsatisfactory results, such as scarring, curvature, or formation of urethral fistulas, diverticula, or strictures. A fistula is an unwanted opening through the skin along the course of the urethra, and can result in urinary leakage or an abnormal stream. A diverticulum is an "outpocketing" of the lining of the urethra which interferes with urinary flow and may result in post-urination leakage. A stricture is a narrowing of the urethra severe enough to obstruct flow. Reduced complication rates even for third degree repair (e.g., fistula rates below 5%) have been reported in recent years from centers with the most experience, and surgical repair is now performed for the vast majority of infants with hypospadias.

Because of the difficulties and lower success rates of surgical repair of the most severe degrees of under virilization, some of these genetically male but severely undervirilized infants have been assigned and raised as girls, with feminizing surgical reconstruction. Opinion has shifted against this approach in the last decade because adult sexual function as a female has often been poor, and development of a male gender identity despite female sex assignment and rearing, has occurred in some XY children after reassignment for a more severe type of genital birth defect, cloacal exstrophy.

Associated birth defects
Mild hypospadias most often occurs as an isolated birth defect without detectable abnormality of the remainder of the reproductive or endocrine system. However, a minority of infants, especially those with more severe degrees of hypospadias will have additional structural anomalies of the genitourinary tract. Up to 10% of boys with hypospadias have at least one undescended testis, and a similar number have an inguinal hernia. An enlarged prostatic utricle is common when the hypospadias is severe (scrotal or perineal), and can predispose to urinary tract infections, pseudo-incontinence, or even stone formation.

Epispadias
A much rarer and unrelated type of urethral malformation is an epispadias. This is not a problem of the urethral groove or meatus, but a failure of midline penile fusion much earlier in embryogenesis. An isolated opening of the dorsal ("top") side of the penis is rare, and most of these children have much more severe defects, involving a small and bifid phallus with bladder exstrophy or more severely, cloacal exstrophy involving the entire perineum. The cause of this defect of early embryogenesis is unknown but does not involve androgens.