J Clin Endocrinol Metab. 2022 Oct 21:dgac615. doi: 10.1210/clinem/dgac615. Online ahead of print.
ABSTRACT
CONTEXT: Isolated hypogonadotropic hypogonadism (IHH) is phenotypically and genetically heterogeneous.
OBJECTIVE: To determine the correlation between genotypic severity with pubertal and neuroendocrine phenotypes in IHH men.
DESIGN: Retrospective study (1980-2020) examining olfaction (Kallmann syndrome [KS] vs. normosmic IHH [nIHH]), baseline testicular volume (absent vs. partial puberty), neuroendocrine profiling (pulsatile vs. apulsatile LH secretion), and genetic variants in 62 IHH-associated genes through exome sequencing (ES).
RESULTS: In total, 242 men (KS: n = 131 [54%], nIHH: n = 111 [46%]) were included. Men with absent puberty had significantly lower gonadotropin levels (p < 0.001) and were more likely to have undetectable LH (p < 0.001). Logistic regression showed partial puberty as a significant predictor of pulsatile LH secretion (R2 = 0.71, p < 0.001, OR: 10.8 [95%CI: 3.6, 38.6]). Serum LH of 2.10 IU/L had a 95% true positive rate for predicting LH pulsatility. Genetic analyses in 204/242 IHH men with ES data available revealed 36/204 (18%) men carried protein truncating variants (PTVs) in 12 IHH genes. Men with absent puberty and apulsatile LH were enriched for oligogenic PTVs (p < 0.001), with variants in ANOS1 being the predominant PTV in this genotype-phenotype association. Men with absent puberty were enriched for ANOS1 PTVs compared to partial puberty counterparts (p = 0.002). PTVs in other IHH genes imparted more variable reproductive phenotypic severity.
CONCLUSIONS: Partial puberty and LH ≥ 2.10 IU/L are proxies for pulsatile LH secretion. ANOS1 PTVs confer severe reproductive phenotypes. Variable phenotypic severity in the face of severe genetic variants in other IHH genes point to significant neuroendocrine plasticity of the HPG axis in IHH men.
PMID:36268624 | DOI:10.1210/clinem/dgac615
