FSH and Sertoli cell biomarkers accurately distinguish hypogonadotropic hypogonadism from self-limited delayed puberty.

Abstract

Context: Delayed puberty is a frequent complaint in males. The differential diagnosis between self-limited delayed puberty (SLDP) and congenital hypogonadotropic hypogonadism (CHH) is challenging. Commonly used endocrine tests, focusing on stimulated levels of luteinizing hormone (LH) or testosterone, are not satisfactory in making a diagnosis. Because FSH action on Sertoli cells results in testis enlargement and anti-Müllerian hormone (AMH) and inhibin B increased secretion, and the FSH-Sertoli cell axis function is detectable during normal childhood and early puberty, we tested whether the assessment of serum FSH, AMH and inhibin B would be informative to distinguish between SLDP and CHH.

Design: We performed a prospective, nested case-control study, in a cohort of male adolescents presenting with delayed puberty, comparing baseline serum reproductive hormone levels to identify predictive biomarkers of CHH, after having followed all participants prospectively until a final diagnosis was ascertained based on gold standard criteria (age 18 years or ≥4 years after testis volume reached 4 mL).

Results: Of 65 participants who completed follow-up, 33 had a final diagnosis of SLDP and 32 of CHH. Serum FSH, AMH and inhibin B showed better diagnostic efficiency than LH and testosterone for these differential diagnoses. FSH (IU/L) x inhibin B (ng/mL) <92 and FSH (IU/L) x AMH (pmol/L) <537 showed high sensitivity (>93%), specificity (≥92%), predictive values (>92%) and positive likelihood ratio (>12) for CHH. The diagnostic performance remained 89.7% and 88.2% for FSH x inhibin B and FSH x AMH, respectively, when analyzed in patients without red flags (micropenis, cryptorchidism and/or microorchidism).

Conclusions: Serum FSH combined with inhibin B or AMH is highly predictive to accurately distinguish between SLDP and CHH in adolescent males.