Endocrine outcome and seminal parameters in young adult men born with hypospadias: A cross-sectional cohort study
Lloyd J.W. Tack,
Anne-Françoise Spinoit,
Piet Hoebeke,
Stefan Riedl,
Alexander Springer,
Ursula Tonnhofer,
Manuela Hiess,
Julia Weninger,
Ahmed Mahmoud,
Kelly Tilleman,
Erik Van Laecke,
Anders Juul,
Jakob Albrethsen,
Elfride De Baere,
Julie Van De Velde,
Hannah Verdin,
Martine Cools
Affiliations
Lloyd J.W. Tack
Department of Internal Medicine and Pediatrics, Ghent University and Pediatric Endocrinology Service, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium
Anne-Françoise Spinoit
Department of Urology, Ghent University Hospital, Ghent University, Ghent, Belgium
Piet Hoebeke
Department of Urology, Ghent University Hospital, Ghent University, Ghent, Belgium
Stefan Riedl
Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; St Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
Alexander Springer
Department of Pediatric Surgery, Medical University of Vienna, Vienna, Austria
Ursula Tonnhofer
Department of Pediatric Surgery, Medical University of Vienna, Vienna, Austria
Manuela Hiess
Department of Pediatric Urology Ordensklinikum Linz, Hospital of the Sisters of Charity, Linz, Austria
Julia Weninger
Department of Pediatric Surgery, Medical University of Vienna, Vienna, Austria
Ahmed Mahmoud
Department of Endocrinology/Andrology, University Hospital Ghent, Ghent, Belgium
Kelly Tilleman
Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium
Erik Van Laecke
Department of Urology, Ghent University Hospital, Ghent University, Ghent, Belgium
Anders Juul
Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
Jakob Albrethsen
Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Elfride De Baere
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
Julie Van De Velde
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
Hannah Verdin
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
Martine Cools
Department of Internal Medicine and Pediatrics, Ghent University and Pediatric Endocrinology Service, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium; Corresponding author.
Summary: Background: Hypospadias affects around 1/200 newborn males. Intrauterine testicular dysfunction may underlie a subset of cases. The long-term endocrine and reproductive outcomes in these men remain largely unknown. Methods: Cross-sectional study in Ghent and Vienna University Hospitals to assess the endocrine and seminal parameters of young adult men (16–21 years) born with non-syndromic hypospadias (NSH) (n = 193) compared to healthy typical males (n = 50). Assessments included physical exam, semen analysis, hormone assays and exome-based gene panel analysis (474 genes). Findings: All participants had experienced a spontaneous puberty, in spite of higher LH and INSL3 levels than typical males. Oligo- or azoospermia was observed in 32/172 (18·6%; 99%-CI: 12·2–27·4%) of NSH men; but in 5/16 (31·3%; 99%-CI: 11·1;62·4%) of complex NSH men and in 13/22 (59·1%; 99%-CI: 33·2–80·7%) of those born small for gestational age (SGA). No (likely) pathogenic coding variants were found in the investigated genes. Suboptimal statural growth affected 8/23 (34·8%; 99%-CI: 15·4–61·0%) of men born SGA with NSH. Interpretation: Spermatogenesis is significantly compromised in NSH men, especially in those born SGA or those with complex NSH. Long-term andrological follow-up is recommended, including end-pubertal semen analysis. No clear monogenic causes could be demonstrated in our cohort even in proximal or complex NSH. Being born SGA with NSH is frequently associated with poor catch-up growth, requiring growth hormone therapy in some. Funding: Research grants from the European Society of Paediatric Endocrinology, the Belgian Society of Pediatrics, the Belgian Society of Pediatric Endocrinology and Diabetology and the Research Foundation Flanders (FWO).
