Serum Concentrations and Gonadal Expression of INSL3 in Eighteen Males With 45,X/46,XY Mosaicism

Abstract

ObjectiveInsulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism.MethodsRetrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included. Biochemical, clinical, and histological outcomes were evaluated according to serum INSL3 concentrations, quantified by LC-MS/MS methodology, and gonadal INSL3 immunohistochemical expression.ResultsSerum INSL3 concentrations spanned from below to above the reference range. In untreated patients, the median serum INSL3 SD score was -0.80 (IQR: -1.65 to 0.55) and no significant difference was observed between INSL3 and testosterone. There was no clear association between serum INSL3 and External Genitalia Score at diagnosis, spontaneous puberty, or sperm concentration. INSL3 and CYP11A1 expression overlapped, except for less pronounced INSL3 expression in areas with severe Leydig cell hyperplasia. No other apparent links between INSL3 expression and histological outcomes were observed.ConclusionsIn this pilot study, serum INSL3 concentrations ranged and seemed independent of other reproductive hormones and clinical features in males with 45,X/46,XY mosaicism. Discordant expression of INSL3 and CYP11A1 may explain low INSL3 and normal testosterone concentrations in some patients. Further studies are needed to elucidate the divergence between serum INSL3 and testosterone and the potential clinical use of INSL3.

Individuals with numerical and structural variations of sex chromosomes: interdisciplinary management with focus on fertility potential

“…Histological examination of spermatogenesis found no germ cells in 50% of post-pubertal boys with the karyotype, arrested spermatogenesis in 25% and spermatids in 25% (31,65). Semen analysis showed azoospermia for most, in line with other studies that have also noted a high proportion with azoospermia (34,35,37,65).…”

“…Spontaneous puberty and normal pubertal progression is reported for many boys with this mosaic karyotype, but testicular function may decline over time (31,35,36,56,103). Histological examination of spermatogenesis found no germ cells in 50% of post-pubertal boys with the karyotype, arrested spermatogenesis in 25% and spermatids in 25% (31,65). Semen analysis showed azoospermia for most, in line with other studies that have also noted a high proportion with azoospermia (34,35,37,65).…”

“…There is increasing evidence that boys who have a 45,X/46,XY karyotype may have similar and equally frequent features and comorbidities as girls who have this karyotype, including cardiac, ear/ nose/throat and renal problems, and dysmorphic features (30,31,34,56). Boys and girls with this karyotype have increased risk of gonadal germ cell cancer, requiring appropriate gonadal management on a case-by-case basis (33,35,65,66). One risk factor related to development of gonadal germ cell cancer is the presence of the testis specific protein on the Y chromosome (TSPY) gene, located on Yp (66).…”