Long-term outcomes of hypospadias : urological and psychosexual function and endocrine-reproductive capacity

Male genital development is a complex process requiring the intricate and delicate interaction of genetic, hormonal and mechanical factors. It is therefore unsurprising that male genital development frequently hampers, commonly presenting with some form of hypospadias. Although roughly 1/200 newborn males is born with hypospadias, very little is known regarding their long-term outcomes. This gap in knowledge renders surgical, endocrine, fertility and genetic counseling of patients and parents difficult. Performing long-term outcome studies is imperative to be able to provide tailored follow-up and guidance to men born with hypospadias and their parents. The main aim of this PhD thesis was to explore the outcome of young men born with various forms of non-syndromic hypospadias and elucidate the genetic factors underlying the development of hypospadias. The first part of the thesis reports the androgen receptor (AR) expression in 428 human foreskin samples, of which 197 from boys who underwent hypospadias repair. Immunohistochemical AR staining was assessed using the mQuicks. This new semi-quantitative method was based on the Quick score used to assess receptor status in breast cancer. Our results showed no differences in AR expression between boys born with hypospadias, versus healthy controls, nor versus boys with buried penis. Instead, age was found to be the principle determinant of AR expression, correlating with the phases in life during which there are high androgen levels (i.e. minipuberty and puberty). Although we failed to find differences in AR expression, these data do not exclude impaired AR functionality or downstream defects. However, based on our data, when exploring the role of the AR in the development of hypospadias, strict age matching appears to be crucial. The following parts mainly used the cross-sectional data of a large cohort of 193 adolescents and young adults born with various forms of non-syndromic 10 hypospadias compared to 50 healthy male peers. The data of this cross-sectional study were divided into three sections. The first part explored the psychosexual outcome and patient and parental satisfaction after hypospadias repair. The overall psychosexual outcome did not show large differences with the control group. However, a negative impact of surgical re-interventions was seen. In addition, patients were generally more content with their genital appearance compared to the physician. As a conclusion we recommend, a restrictive attitude towards re-interventions for non-functional problems. Mild erectile and ejaculatory problems were seen in 10% of cases, but appeared unrelated to any patient or surgical factors. The majority of patients and parents were content with the childhood hypospadias repair. However, many parents indicated that they had experienced the entire diagnostic and therapeutic process as very stressful, warranting the organization of early psychological support for parents who need it. The second part assessed the surgical and urological outcome of the same cohort. Re-interventions were needed in 39.2%, whereas suboptimal urinary and/or sexual outcomes were found in 52.9% of cases. Several factors were found to be associated with more re-interventions and poor urological outcomes. Our data support the organization of a specialized urology team for hypospadias repair and deferral of hypospadias repair until the age of at least 12 months. Smaller adult stretched penile lengths and more severe hypospadias were also associated with worse outcomes and warrant a cautious approach in order to avoid complications. Our data also support the routine use of uroflowmetry during follow-up well into adulthood, as suboptimal voiding was common. The third part explored the endocrine outcome and semen characteristics, as well as the genetic mechanisms involved in the development of hypospadias and poor outcomes in some. Additional data focusing on growth, hormone levels during minipuberty and puberty in boys born small for gestational age (SGA) and appropriate for gestational age (AGA) with severe 11 hypospadias were provided through a supplementary retrospective study using the I-DSD registry. These studies revealed poor growth in those born SGA with hypospadias at three times the rate as what has been reported in the overall SGA population (i.e. 30%). Hormone levels during minipuberty suggested infantile Leydig cell dysfunction in SGA children, whereas evidence was found of subclinical adult Leydig cell dysfunction in the entire hypospadias population. In addition, low sperm counts were a point of concern in hypospadias cases, especially in those born SGA or AGA with complex hypospadias (60% and 30%, respectively). The cause of the frequent testicular dysfunction in men born with hypospadias appeared to be multifactorial and largely dependent on environmental and perhaps epigenetic factors as no mono- or oligogenic causes were identified in the genetic study