Transient Gonadotropin Suppression by Exogenous Testosterone Decreases INSL3 in Early Puberty in boys with CDGP

Abstract We investigated circulating insulin-like peptide 3 (INSL3) in boys with constitutional delay of growth and puberty (CDGP) treated with exogenous testosterone (T) or oral letrozole (Lz). Twenty-eight boys were randomized to Lz (2.5 mg/day; n=15) or intramuscular T (1 mg/kg every 4 weeks; n=13) for six months and followed up to 12 months. Blood samples were collected at baseline and at 3, 6, and 12 months to measure INSL3 and other pubertal hormones (ClinicalTrials.gov NCT01797718). At baseline, INSL3 levels were similar between groups (T: 1.4 ng/ml [0.8], Lz: 1.9 ng/ml [1.8], p=0.39). T suppressed LH, FSH, and INSL3 between 0 and 3 months (p<0.01), and changes in INSL3 correlated with changes in LH (r=0.61, p<0.001) and FSH (r=0.67, p<0.001). Between 3 and 6 months, INSL3 and gonadotropins rose in the T group, while both increased from 0 to 6 months with Lz (p<0.001). At 12 months, INSL3 levels did not differ between groups. Exogenous testosterone thus transiently suppresses INSL3 via gonadotropin inhibition in early puberty.