Hypospadias and endocrine disruption: is there a connection? (Children's Health Review).

Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 250 newborns or roughly 1 in 125 live male births. It is the result of arrested development of the urethra, foreskin, and ventral surface of the penis where the urethral opening may be anywhere along the shaft, within the scrotum, or in the perineum. The only treatment is surgery. Thus, prevention is imperative. To accomplish this, it is necessary to determine the etiology of hypospadias, the majority of which have been classified as idiopathic. In this paper we briefly describe the normal development of the male external genitalia and review the prevalence, etiology, risk factors, and epidemiology of hypospadias. The majority of hypospadias are believed to have a multifactorial etiology, although a small percentage do result from single gene mutations. Recent findings suggest that some hypospadias could be the result of disrupted gene expression. Discoveries about the antiandrogenic mechanisms of action of some contemporary-use chemicals have provided new knowledge about the organization and development of the urogenital system and may provide additional insight into the etiology of hypospadias and direction for prevention. Key words: antiandrogens, differentiation, external genitalia, gene expression, urogenital development. Environ Health Perspect 109:1175-1183 (2001). [Online 7 November 2001] http://ehpnet1.niehs.nih.gov/docs/2001/109p1175-1183baskin/abstract.html

Hypospadias is one of the most common congenital anomalies in the United States; it occurs in approximately 1 in 250 newborns or roughly 1 in 125 live male births (1,2). Hypospadias can be defined as an arrest in normal development of the urethral, foreskin, and ventral aspect of the penis. This results in a wide range of abnormalities, with the urethral opening being anywhere along the shaft of the penis, within the scrotum, or even in the perineum (3). The more severe forms of hypospadias are associated with penile curvature. Left uncorrected, patients with severe hypospadias may need to sit down to void and tend to shun intimate relationships because of the fears related to abnormal sexuality. Babies born with severe hypospadias and penile curvature may have "ambiguous genitalia" in the newborn period, making an immediate accurate sex assignment difficult.

The only treatment for hypospadias is surgical repair of the anatomical defect (3). Reconstruction, if performed by an experienced surgeon, generally involves a single outpatient procedure (3,4). Occasionally, however, extensive surgery is required, or patients may face "redo" surgeries to improve suboptimal results (5). There is significant morbidity associated with some surgical procedures to correct hypospadias as well as potential psychosocial consequences of having an abnormal genital (6,7). In addition to the difficulty of surgery, the emotional and physical stress for the parents of patients with ambiguous genitalia must be considered (8).

In this paper we explore the hypothesis that hypospadias may in part be the result of exposure to synthetic and/or natural chemicals that can perturb normal male development. The fetus is especially sensitive to these chemicals known as endocrine disruptors that can mimic or interfere with the natural hormones that control development. We provide a brief description of normal development of the male external genitalia and review the prevalence, etiology, risk factors, and epidemiology of hypospadias. We also present evidence concerning the effects of recently discovered xenobiotic antiandrogens on the development of the male urogenital system.

Classification of Hypospadias

Hypospadias is classified depending on the location of the urethral opening (meatus) (Figure 1) (3). Anterior hypospadias is described as glandular (meatus on the inferior surface of the glans penis; Figure 1A), coronal (meatus in the balanopenile furrow; Figure 1B), or distal (in the distal third of the shaft; Figure 1C). Middle hypospadias is along the middle third of the penile shaft. Posterior hypospadias extends through the proximal third of the penile shaft to the perineum and is described as posterior penile (at the base of the shaft), penoscrotal (at the base of the shaft in front of the scrotum; Figure 1D), scrotal (on the scrotum or between the genital swellings; Figure 1E), or perineal (behind the scrotum or behind the genital swellings; Figure 1F). Chordee or penile curvature is a downward curvature of the penis that typically accompanies the more severe forms of hypospadias. Standard classification of hypospadias does not take into account the associated penile curvature. A patient with severe curvature and an anterior urethral meatus may in fact require a more extensive surgery to correct both the curvature and the abnormal urethra.

[FIGURE 1 OMITTED]