Risk of Urological Cancer Among Boys and Men Born with Hypospadias: A Swedish Population-based Study.

Background: Hypospadias is a common genital malformation among boys. Studies indicate that hypospadias is associated with a higher risk of testicular cancer. Other forms of urological cancer may be linked to hypospadias via a mutual aetiology, hormonal dysfunction, or hypospadias complications, but this has not yet been studied. Objective: To investigate the association between hypospadias and testicular cancer and the risk of other urological cancers among individuals born with hypospadias. Design setting and participants: The study used a population-based male cohort born in Sweden in 1964-2018. Exposure was hypospadias diagnosis in national registers. Outcomes were defined using the Swedish Cancer Register. An extended cohort born from 1940 was used to study cancers among older men. Biological brothers and fathers were linked to investigate familial coaggregation. Outcome measurements and statistical analysis: Associations were assessed using Cox proportional-hazards regression analysis, with results presented as hazard ratios. Results and limitations: We found that hypospadias was associated with a higher risk of testicular cancer (hazard ratio 2.04, 95% confidence interval 1.42-2.92), especially for proximal hypospadias, but did not observe any clear familial coaggregation of hypospadias and testicular cancer. Hypospadias was associated with Wilms' tumour in childhood. We also found an association between hypospadias and bladder and urethral cancers, but not prostate cancer. The number of cases with hypospadias was small and the results for cancers among older men may be impacted by limitations in register coverage. Conclusions: Our study supports the hypothesis of a higher risk of testicular cancer for men with hypospadias, especially with proximal phenotypes. Hypospadias may also be associated with a higher risk of lower urinary tract cancers, although this requires further investigation in older cohorts. Patient summary: Boys and men in whom the opening of the urethra is not at the end of the penis (called hypospadias) at birth are at higher risk of developing testicular cancer, although their overall risk is still low. They may also have a higher risk of developing other forms of cancer in the urinary tract.

A qualitative content analysis of the experience of hypospadias care: The importance of owning your own narrative.

Objectives: There is a lack of studies on men's individual experiences of living with hypospadias. We aimed to explore the personal experiences of having hypospadias in relation to healthcare and surgery. Subjects and methods: Purposive sampling was used to include men (aged 18 and over) with hypospadias representing different phenotypes (from distal to proximal) and ages in order to maximise the variation and richness of our data. Seventeen informants, aged 20-49, were included in the study. In-depth semi-structured interviews were conducted between 2019 and 2021. Inductive qualitative content analysis was used to analyse the data. Results: We identified three categories: (1) Having surgery, which comprised the decision to operate, the experience of having surgery, and the outcomes of surgery; (2) Going to the doctor, which focused on follow-up care, re-entering care in adolescence or adulthood, and the experience of healthcare interactions; (3) Being informed, both about hypospadias in general, as well as about your specific body and medical history. There was overall a large variation in experiences. The latent theme across the data was the importance of owning your own narrative. Conclusion: The experience of men with hypospadias in healthcare is complex and varied, highlighting the difficulty of fully standardised care. Based on our results, we suggest that follow-up should be offered in adolescence, and that ways of accessing care for late onset complications be made clear. We further suggest clearer consideration for the psychological and sexual aspects of hypospadias. Consent and integrity in all aspects and all ages of hypospadias care should be adapted to the maturity of the individual. Access to trustworthy information is key, both directly from educated healthcare staff and if possible, from websites or patient-led forums. Healthcare can play a key role in providing the growing individual with tools to understand and address concerns that may develop relating to their hypospadias through life, giving them ownership over their own narrative.

Increased androgen-related comorbidity in adolescents and adults born with hypospadias: A population-based study.

BACKGROUND: Hypospadias is a common congenital malformation often related to the effect of androgens in utero. While hypogonadism is associated with many potential health risks including metabolic and cardiovascular disease, the risk of clinical hypogonadism and comorbidities in men with hypospadias later in life has not been studied. OBJECTIVES: Investigate the risk of hypogonadism and somatic comorbidities in adolescents and men born with hypospadias. MATERIALS AND METHODS: We conducted a population-based cohort study using Swedish registers. Associations between hypospadias and hypogonadism, delayed puberty, metabolic, and cardiovascular disease respectively were estimated using Cox proportional hazards regression. Body measurements from military conscription were analysed in a subpopulation as indicators of growth and cardiometabolic risk. We used sibling comparison analyses to control for familial confounding. RESULTS: Using register data, a total of 2,165,255 men including 9,714 men born with hypospadias were followed from the age of 10 to a maximum of 60 years. We found an association between hypospadias and hypogonadism (Hazard ratio (HR) 3.27, 95% confidence interval (CI) 2.33-4.59) which was more pronounced in proximal hypospadias. Men with hypospadias had shorter average height than their brothers and the general population. We further found an increased risk of delayed puberty (HR 1.49, 95% CI 1.08-2.07), diabetes mellitus type 2 (HR 1.57, 95% CI 1.18-2.09) and cardiovascular disease (HR 1.47, 95% CI 1.27-1.71). DISCUSSION: We found an increased risk of hypogonadism, metabolic and cardiovascular disease in men born with hypospadias, increasing with severity of phenotype, as well as impacted growth. These results indicate discruptions in androgen function past childhood, although some of the associations may be due to other underlying aetiologies. CONCLUSION: Hypospadias is associated with an increased risk of androgen-related comorbidity in adolescence and adulthood. We suggest that this can be considered clinically, while further research is needed, especially in older populations.

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

BACKGROUND: It is not known if impaired fertility in men with hypospadias is caused by decreased semen quality or other factors. Semen quality in men born with hypospadias may be impaired due to effects of androgens or testicular dysgenesis but has been very little studied. OBJECTIVES: To study semen quality in men with hypospadias using dizygotic twinning rates as an epidemiological indicator. We further aimed to study men treated for cryptorchidism, given a hypothesized mutual etiology for decreased semen quality. MATERIALS AND METHODS: We conducted a population-based study using national Swedish registers. A total of 4,363,165 births between 1964 and 2013 were included. The association between hypospadias and cryptorchidism, and fathering dizygotic multiple births was estimated using logistic regression and presented as odds ratios. The main analyses excluded births conceived using assisted reproductive technology (ART). RESULTS: We identified a total of 5317 births with fathers with hypospadias, including 26 dizygotic births conceived unassisted. No significant association was found between hypospadias and dizygotic twinning (OR 1.10, 0.75-1.61). We estimated a significantly increased odds for dizygotic multiple births in men treated for cryptorchidism (OR 1.35, 1.01-1.81) which was decreased after exclusion of ART, but the estimate was not significant (OR 0.75, 0.48-1.18). DISCUSSION: Using dizygotic twinning rates as an indicator of semen quality, we did not find any difference between fathers with hypospadias and controls. Due to sample size, we could not analyze phenotypes separately and can therefore not exclude impaired semen quality in severe hypospadias. We could not demonstrate any association between dizygotic twinning and cryptorchidism. Men treated for cryptorchidism were more likely than controls to use ART to conceive. CONCLUSION: Men with hypospadias who conceived without ART were not shown to have impaired semen quality using dizygotic twinning as an epidemiological indicator.

Doxorubicin-provoked increase of mitotic activity and concomitant drain of G0-pool in therapy-resistant BE(2)-C neuroblastoma.

In this study chemotherapy response in neuroblastoma (NB) was assessed for the first time in a transplantation model comprising non-malignant human embryonic microenvironment of pluripotent stem cell teratoma (PSCT) derived from diploid bona fide hESC. Two NB cell lines with known high-risk phenotypes; the multi-resistant BE(2)-C and the drug sensitive IMR-32, were transplanted to the PSCT model and the tumour growth was exposed to single or repeated treatments with doxorubicin, and thereafter evaluated for cell death, apoptosis, and proliferation. Dose dependent cytotoxic effects were observed, this way corroborating the experimental platform for this type of analysis. Notably, analysis of doxorubicin-resilient BE(2)-C growth in the PSCT model revealed an unexpected 1,5-fold increase in Ki67-index (p<0.05), indicating that non-cycling (G0) cells entered the cell cycle following the doxorubicin exposure. Support for this notion was obtained also in vitro. A pharmacologically relevant dose (1µM) resulted in a marked accumulation of Ki67 positive BE(2)-C cells (p<0.0001), as well as a >3-fold increase in active cell cycle (i.e. cells positive staining for PH3 together with incorporation of EdU) (p<0.01). Considering the clinical challenge for treating high-risk NB, the discovery of a therapy-provoked growth-stimulating effect in the multi-resistant and p53-mutated BE(2)-C cell line, but not in the drug-sensitive p53wt IMR-32 cell line, warrants further studies concerning generality and clinical significance of this new observation.