Lifelong health and well-being in men born with hypospadias

Hypospadias is a congenital malformation defined by an ectopic placement of the urethral orifice along the ventral side of the penis, with a large variation in phenotype from distal to proximal. There are both genetic and environmental risk factors, often related to an impact on androgen function which is central in the development of male genitalia. Treatment is surgical, focusing on extending the urethra and straightening penile curvature. Complications are more common following proximal hypospadias surgery, including urethral fistulas and strictures, while distal cases generally have positive outcomes. In Sweden, follow-up typically continues until a maximum age of 15, and globally most boys are not followed into adulthood. This, together with a lack of studies, limits the knowledge about long-term outcomes in boys and men with hypospadias, especially those of middle and old age.

This PhD project aimed to study lifelong health and well-being in men born with hypospadias. Study I-III used population-based epidemiological designs and Swedish register data. Study IV and V used in-depth interviews to collect data from 17 adult informants which was analysed using qualitative content analysis.

In study I, we investigated fertility. Prior research has indicated impaired fertility in men with hypospadias, but there are several different potential causes. Using dizygotic twinning as an epidemiological indicator of male fecundity, we found no significant association with hypospadias, indicating a limited impact on semen quality overall. However, subpopulations of men with hypospadias may have significantly impaired fecundity.

In study II, we investigated the risk of androgen-related disease. We found an increased risk of hypogonadism, especially in those with proximal hypospadias, as well as an increased risk of delayed puberty, diabetes mellitus type 2, and cardiovascular disease, but no association with obesity overall. We also found an association with somewhat decreased adult height. The associations were not fully explained by comorbidity with other congenital conditions, by prenatal factors, or by shared familial factors, but they may be multifactorial, encompassing these different mechanisms to varying degrees.

In study III, we investigated the risk of urological cancer in boys and men born with hypospadias. We found an increased risk of testicular cancer, in line with previous research. The risk was highest in men with proximal hypospadias. We did not find a significant increase in risk of testicular cancer in fathers or brothers of those with hypospadias. We further found an increased risk of Wilms’ tumour in childhood, as well as lower urinary tract cancer in adults, but no significant association with prostate cancer.

In study IV, we explored the personal experience of hypospadias care. We found that experiences are complex and varied. Our results highlighted the importance of considering aesthetics, sexual function, and psychological well-being, in addition to voiding function, in surgery and follow-up care. Further important areas were particular support in adolescence, how and why to seek help, access to reliable information, and clear and empathetic communication, adapted to the maturity of the patient.

In study V, we explored the experience of hypospadias in relation to identity and interpersonal relationships. While well-being could be largely unaffected, some informants described recurring social and sexual avoidance and insecurity. The complex personal experience of being born with hypospadias varied with overall impact and coping, in relation to both internal factors and experiences, including physical outcomes, and interpersonal context.

List of scientific papers

I. Phillips L, Lundholm C, Örtqvist L, Almqvist C, Nordenskjöld A, Skarin Nordenvall A. Fertility in men with hypospadias: A nationwide register-based study using dizygotic twinning rates as an indicator of semen quality. Andrology. 2021 May;9(3):810-816.
https://doi.org/10.1111/andr.12975

II. Phillips L, Lundholm C, Kvist U, Almqvist C, Nordenskjöld A, Skarin Nordenvall A. Increased androgen-related comorbidity in adolescents and adults born with hypospadias: A population-based study. Andrology. 2022 Oct;10(7):1376-1386.
https://doi.org/10.1111/andr.13229

III. Phillips L, Lundholm C, Almqvist C, Skarin Nordenvall A, Nordenskjöld A. The risk of urological cancer in boys and men born with hypospadias: a Swedish population-based study. [Submitted]

IV. Phillips L, Dennermalm N, Örtqvist L, Engberg H, Holmdahl G, Fossum M, Möller A, Nordenskjöld A. A qualitative content analysis of the experience of hypospadias care: The importance of owning your own narrative. Frontiers in Pediatrics. 2023 Feb 17;11:1118586.
https://doi.org/10.3389/fped.2023.1118586

V. Phillips L, Dennermalm N, Örtqvist L, Engberg H, Holmdahl G, Fossum M, Möller A, Nordenskjöld A. A qualitative content analysis of the experience of living with hypospadias: varying impact on identity and interpersonal relationships. [Manuscript]