Endocrinol Diabetes Metab. 2026 Sep;9(5):e70317. doi: 10.1002/edm2.70317.
ABSTRACT
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.
PMID:42682192 | DOI:10.1002/edm2.70317
