Gonadotropin Suppression During Mini-Puberty as an Early Biomarker of Classic 21-Hydroxylase Deficiency.

INTRODUCTION

Newborn screening (NBS) for congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (21OHD) relies on elevated 17-hydroxyprogesterone (17OHP) levels but is limited by a high false-positive rate and difficulty in distinguishing classic from non-classic forms. To evaluate whether the suppression of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during mini-puberty can serve as an early biomarker of classic 21OHD.

METHODS

We conducted a retrospective cohort study of 37 infants evaluated for suspected 21OHD between 2013 and 2025. Subjects were classified as classic (C), non-classic (NC), or false-positive (FP) based on biochemical and genetic confirmation. Neonatal serum LH and FSH levels were compared among groups, and receiver operating characteristic (ROC) analyses were performed.

RESULTS

LH and FSH levels were significantly suppressed in classic 21OHD compared with NC and FP cases (p < 0.001). Gonadotropin concentrations demonstrated a stepwise pattern (C<NC<FP), although overlap limited the discrimination of non-classic disease. ROC analyses identified optimal cutoff values of 0.3 mIU/mL for LH (sensitivity 89.5%, specificity 83.3%) and 1.3 mIU/mL for FSH (sensitivity 94.7%, specificity 100%) for identifying classic 21OHD. Suppression was observed in both sexes and was particularly informative in male neonates.

CONCLUSIONS

Suppressed LH and FSH levels during the neonatal period reflect the attenuation of mini-puberty and represent a characteristic endocrine feature of classic 21OHD. Gonadotropin measurement may provide a clinically accessible adjunct to NBS for the early identification of severe disease, particularly in male neonates and in the evaluation of 46,XX disorders/differences in sex development.