Register-based studies of hypospadias

Abstract: Hypospadias is a common genital malformation ofcomplex origin. It is characterized by misplacement of the urethral orifice, proximal to the tip of the glans penis, and is most often accompanied by a cleaved prepuce and varying degrees of ventral penile curvature. The phenotype ranges from distal hypospadias, where the misplacement of the urethral orifice is small, to more proximal cases where the urethral orifice may be located in the perineum and lead to uncertain sex at birth. This thesis aims to elucidate aspects of the etiology, and increase the knowledge concerning the consequences of being born with hypospadias. All studies are based on information collected from national population-based Swedish registers, containing healthcare and demographic data. In Study I we investigated associated risk factors, in terms of parental and perinatal characteristics, and the prevalence of hypospadias. We found an increased prevalence of boys assigned with hypospadias during the late 20th century. Further, we found that boys born small for gestational age, as twins, as a result of ART, or by parents from greater Europe (excluding the Nordic countries) or Asia were at an increased risk of being registered with a diagnosis of hypospadias. The trend in prevalence was not attributable to temporal changes in the investigated risk factors. Study II highlighted the association between hypospadias and the neuromuscular disorder known as spinal-bulbar muscle atrophy (SBMA), for which the common denominator is a CAG repeat expansion in the androgen receptor (AR) gene. We described one clinical case; a boy born with proximal hypospadias who was found to have 42 CAG repeats in the AR gene, which is a mutation known to cause SBMA later in life. In Swedish health care registers we found four potential cases of SBMA and hypospadias in individuals and within families. In Study III we investigated socioeconomic outcomes in men born with hypospadias as a proxy of well-being in adulthood. We found that men born with hypospadias displayed a similar level of education and income, and were as likely to be married as non-affected men. Men with proximal hypospadias did, however, suffer a greater risk of receiving a disability pension. This risk may be due to the effect of unmeasured psychiatric comorbidity, conditions related to androgen deficiency, or hypospadias as a part of unrecognized syndromes. In Study IV we aimed to assess the fertility of adult men born with hypospadias. We found a lower probability of registered paternity among men with hypospadias; the association was most prominent in men with proximal hypospadias and of small magnitude in distal hypospadias. Men with hypospadias were more likely to being diagnosed with male infertility and of conceiving through ART. The overall results imply that fertility is impaired in men with distal and proximal hypospadias, probably as a result of anatomic features, gonadal dysfunction, psychological, or genetic factors.