Endocrine Abstracts

Introduction: Delayed puberty (DP), affecting over 2% of adolescents, is defined as pubertal onset at 2-2.5 SDs later than the general population. Two common underlying aetiologies are self-limited DP (SLDP) and congenital hypogonadotrophic hypogonadism (HH). However, these can be difficult to discern between on first presentation of a patient to endocrinology services. This study sought to elucidate phenotypic and genotypic differences between the two diagnoses in order to optimise patient treatment and pubertal progression.

Methods: This was a retrospective study of a UK DP cohort managed from 2015-2022, identified through the NIHR clinical research network. Patients were diagnosed with SLDP if they had attained Tanner stage G4/B4 by age 18 years. Alternatively, they were diagnosed with HH if they had not commenced (complete, cHH) or had arrested puberty (partial, pHH) prior to age 18 years. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment were analysed. Genetic scores for likelihood of HH were assigned from 1-5 after whole-exome sequencing and identification of predicted pathogenic variants in genes associated with either SLDP or HH (1=known SLDP variant, 2=likely SLDP variant, 3=no or overlap variant, 4=likely HH variant, 5=known HH variant). Statistical analysis was completed using IBM SPSS and R.

Results: 78 patients were included in this study. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight SD than HH patients (P=0.004, P=0.021). HH patients had lower testicular volumes, particularly cHH patients (P=0.019). 23.1% of SLDP and 2.9% of HH patients had a family history of DP (P=0.709). 17.3% of SLDP compared to 34.6% of HH patients had classical symptoms of HH (e.g. micropenis, cryptorchidism, anosmia, renal or limb anomalies, P=0.807). Mean first recorded LH and inhibin B were also lower in HH patients, particularly in cHH patients (P=0.005, P=0.002). Mean genetic score of SLDP patients was lower at 3.00±0.55 as compared to 3.47±0.70 in HH patients (P=0.008). There were no significant differences identified in FSH, testosterone, AMH or bone age delay.

Discussion: This study identifies key phenotypic markers that help distinguish between SLDP and HH on first presentation, and that could be incorporated with genetic scoring to improve diagnostic accuracy. Further research into such an integrated framework or scoring system would be useful in aiding clinician decision-making and treatment optimisation.