Hypospadias: One Defect, Multiple Causes, Acting Through Shared Pathways

Abstract

Hypospadias is one of the most common birth defects among males. Although the birth prevalence of hypospadias has been reported as increasing in some geographic regions, inconsistencies in ascertainment of mild cases and variability in reporting standards are likely contributing to these apparent trends. While hypospadias is highly heritable, there is limited knowledge about the specific genetic and epigenetic factors that play a role in its etiology. Risk factors for hypospadias include family history, older maternal age, nulliparity, high maternal prepregnancy body mass index, hypertension or preeclampsia, multiple gestations, reduced birth weight, and small for gestational age. Of the various prenatal exposures to medications that have been studied, the strongest evidence supports valproic acid as a contributor to hypospadias. Studies evaluating the impact of assisted reproductive technologies (ART) on hypospadias are inconclusive because of potential confounding by subfertility. Many causes of hypospadias may act through a few shared pathways, such as placental dysfunction.

Fertility in men with hypospadias: A nationwide register‐based study using dizygotic twinning rates as an indicator of semen quality

“…Around 10–15% of all patients have proximal hypospadias 2 . Hypospadias has both genetic and environmental risk factors, most of which are known or hypothesized to be related to disruptions in androgen pathways, as the development of external male genitalia is an androgen‐driven process 3 …”