Reproductive Hormones During Minipuberty Suggest Subtle Testicular Impairments in Boys With Hypospadias.

Abstract

Context: The ontogeny of hypospadias and its implications remain incompletely understood.

Objective: To examine whether fetal outcomes and reproductive hormone concentrations in boys with hypospadias differ from reference standards during minipuberty.

Design: Prospective cohort study (May 2021-January 2023).

Setting: Tertiary hypospadias center.

Patients: Infants presenting with hypospadias (n = 139), of whom 113 were enrolled following parental consent (median postnatal age: 0.28 years).

Interventions: Examination of hypospadias grade, external masculinization score (EMS), placental and birth weight, and blood sampling (reproductive hormones).

Main outcome measures: Fisher's exact test assessed gestational age (GA)-specific birth weight and placental centiles by hypospadias severity. GA-specific reproductive hormone concentrations were converted to SD scores (SDSs) according to an established reference standard for healthy Danish boys. The 1-sample Wilcoxon signed-rank test compared concentrations to 0 SDS.

Results: Eighty-nine boys (79%) had distal hypospadias with a median EMS of 11 while median EMS was 9 in boys with proximal hypospadias. Birth weight and placental centiles were lower in boys with proximal hypospadias (P = .014 and P = .038). The median concentrations of FHS (0.83 SDS), testosterone (0.71 SDS), and free testosterone (0.83 SDS) were higher in boys with hypospadias compared to 0 SDS (P < .001). The median concentrations of inhibin B (-0.38 SDS), anti-Müllerian hormone (AMH) (-0.23 SDS), insulin-like factor 3 (INSL3) (-0.31 SDS), androstenedione (-0.52 SDS), and dehydroepiandrosterone sulfate (-0.50 SDS) were significantly lower. LH, SHBG, 17-hydroxyprogesterone, and dihydrotestosterone were not statistically different. Hormone SDS did not differ significantly by hypospadias severity.

Conclusion: Hypospadias severity was significantly associated with birth and placental weight centiles. Testicular Sertoli cell markers (AMH and inhibin B) and the Leydig cell-derived INSL3 were reduced, suggesting subtle testicular dysfunction in boys with hypospadias during minipuberty. Further research to identify implications for future reproductive health is warranted.