Abstract
The incidence of precocious puberty (PP, the appearance of signs of pubertal development at an abnormally early age), is rapidly rising, concurrent with changes of diet, lifestyles, and social environment. The current diagnostic methods are based on a hormone (gonadotropin-releasing hormone) stimulation test, which is costly, time-consuming, and uncomfortable for patients. The lack of molecular biomarkers to support simple laboratory tests, such as a blood or urine test, has been a long standing bottleneck in the clinical diagnosis and evaluation of PP. Here we report a metabolomic study using an ultra performance liquid chromatography-quadrupole time of flight mass spectrometry and gas chromatography-time of flight mass spectrometry. Urine metabolites from 163 individuals were profiled, and the metabolic alterations were analyzed after treatment of central precocious puberty (CPP) with triptorelin depot. A panel of biomarkers selected from >70 differentially expressed urinary metabolites by receiver operating characteristic and logistic regression analysis provided excellent predictive power with high sensitivity and specificity for PP. The altered metabolic profile of the PP patients was characterized by three major perturbed metabolic pathways: catecholamine, serotonin metabolism, and tricarboxylic acid cycle, presumably resulting from activation of the sympathetic nervous system and the hypothalamic-pituitary-gonadal axis. Treatment with triptorelin depot was able to normalize these three altered pathways. Additionally, significant changes in the urine levels of 4-hydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, indoleacetic acid, 5-hydroxytryptophan, and 5-hydroxykynurenamine in the CPP group suggest that the development of CPP condition may involve an alteration in symbiotic gut microbial composition.
Highlights
Puberty, the primary regulator of the reproductive process in vertebrates, is a complex biological process affected by systemic and environmental factors such as activation of the hypothalamic-pituitary-gonadal axis (HPGA)1 [1]
Precocious puberty (PP) can be divided into two types, central precocious puberty (CPP, called “true precocious puberty”) and peripheral precocious puberty (PPP, or “pseudo precocious puberty”), depending on whether or not the HPGA is involved [5]
Because of the lack of molecular biomarkers to support simple laboratory tests, the clinical diagnosis and evaluation of PP has to rely on a hormone (GnRH) stimulation test, which is costly, time-consuming, and uncomfortable for patients [11]
Summary
The primary regulator of the reproductive process in vertebrates, is a complex biological process affected by systemic and environmental factors such as activation of the hypothalamic-pituitary-gonadal axis (HPGA)1 [1]. Because of the lack of molecular biomarkers to support simple laboratory tests, the clinical diagnosis and evaluation of PP has to rely on a hormone (GnRH) stimulation test, which is costly, time-consuming, and uncomfortable for patients [11] To avoid these problems, several attempts, such as measurement of basal gonadotropin levels or subcutaneous leuprolide acetate test with a single sample, have been made [12,13,14]. We profiled urine metabolites in 163 participants using ultra performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLCQTOFMS) and gas chromatography-time of flight mass spectrometry (GC-TOFMS) These two analytical platforms (UPLC-QTOFMS and GC-TOFMS) were used to maximize the number of the detectable metabolites for the evaluation of the phenotypic variations in CPP and PPP subjects and the effect of triptorelin depot intervention.
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