Sweetener Consumption and Genetic Predisposition: New Insights into Early Puberty Risk in Children

Highlights

• Higher intake of aspartame, sucralose, glycyrrhizin, and added sugars is associated with increased risk of central precocious puberty (CPP), especially in children with genetic predisposition.
• Sex-specific associations: sucralose is linked to higher CPP risk in boys, while sucralose, glycyrrhizin, and added sugars increase risk in girls.
• No significant interaction between genetic risk and sweetener intake was found, suggesting independent contributions to CPP risk.
• Findings support dietary and genetic screening in at-risk pediatric populations to guide preventive strategies.

Clinical Background and Disease Burden

Central precocious puberty (CPP) is characterized by the abnormally early onset of secondary sexual characteristics, often before age 8 in girls and 9 in boys. CPP can have profound physical and psychosocial consequences, including compromised adult height, increased risk of metabolic syndrome, and psychological distress. Recent epidemiological data suggest a rising prevalence of CPP globally, with environmental, nutritional, and genetic factors all implicated in its etiology. Identifying modifiable risk factors is critical for developing prevention and intervention strategies.

Methodology

The Taiwan Pubertal Longitudinal Study recruited a cohort of 1407 children to investigate the effect of sweetener intake and genetic susceptibility on CPP risk. Sweetener intake—including aspartame, sucralose, glycyrrhizin (a natural sweetener), and added sugars—was assessed using validated dietary questionnaires and urinary biomarkers to enhance accuracy. Genetic predisposition was quantified using polygenic risk scores (PRS) derived from 19 single-nucleotide polymorphisms (SNPs) previously associated with CPP. Diagnosis of CPP relied on a standardized clinical protocol combining physical examination, hormonal assays, and imaging studies. The study’s endpoints were incidence of CPP and dose-response relationships between sweetener intake, PRS, and CPP risk.

Key Findings

Among 1407 participants, 481 were diagnosed with CPP. The study revealed:

• Significant associations between sweetener intake and CPP risk: Higher intake of aspartame, glycyrrhizin, sucralose, and added sugars was associated with increased CPP risk (p-values <0.05 for all comparisons).
• Genetic predisposition: Children with higher PRS scores had an elevated risk of CPP, independent of dietary intake.
• Dose-dependent relationship: Greater consumption of sweeteners correlated with higher CPP incidence, suggesting a dose–response effect.
• Sex-specific differences: Sucralose intake showed a stronger association with CPP in boys, whereas in girls, sucralose, glycyrrhizin, and added sugars were all significantly associated with higher risk.
• No interaction between genetics and sweetener intake: The effects of sweetener consumption and genetic risk were additive but not synergistic.

Mechanistic Insights

While the precise mechanisms remain under investigation, several hypotheses are plausible. Artificial sweeteners have been shown to alter gut microbiota composition and may influence neuroendocrine signaling, potentially affecting the hypothalamic-pituitary-gonadal (HPG) axis. Glycyrrhizin, derived from licorice root, is known for its endocrine-modulating properties and has been shown in animal models to impact puberty timing via gut microbiome modulation. Genetic susceptibility likely converges on pathways regulating gonadotropin release, amplifying the impact of environmental exposures such as dietary sweeteners.

Expert Commentary

The study authors note: “The findings indicate that sweetener consumption and genetic predisposition are independently associated with CPP risk. Integrating genetic and dietary assessments could guide prevention strategies for children at heightened risk, mitigating the long-term health impacts of early puberty.” These results add to a growing body of evidence prompting clinicians to consider both genetic and lifestyle factors in managing early puberty risk.

Controversies and Limitations

Despite its robust design, several limitations should be acknowledged:

• Observational design: Causality cannot be definitively established.
• Self-reported dietary data: Although complemented by urinary biomarkers, recall bias is possible.
• Ethnic and geographic specificity: The cohort consisted solely of Taiwanese children, possibly limiting generalizability.
• Potential confounders: Other environmental or socio-economic variables may influence puberty timing.

Further studies are needed to elucidate mechanisms and to determine whether intervention on sweetener consumption can modify CPP risk in genetically susceptible populations.

Conclusion

This large, prospective cohort study underscores the independent and additive roles of sweetener intake and genetic predisposition in the risk of central precocious puberty. The sex-specific associations highlight the need for tailored dietary counseling and genetic risk assessment. For clinicians, incorporating screening for dietary habits and family/genetic risk may support early intervention and prevention strategies to mitigate the long-term sequelae of early puberty.

References

1. Nguyen NN, Lin CY, Tsai WL, Huang HY, Chen CM, Tung YT, Chen YC. Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome. Life Sci. 2024 Aug 1;350:122789. doi: 10.1016/j.lfs.2024.122789.

2. Wu HT, Chiang CC, Wang CT, Chen YH, Hsu SY, Chen YC. Consumption of the nonnutritive sweetener acesulfame potassium increases central precocious puberty risk. J Hazard Mater. 2024 Jan 5;461:132529. doi: 10.1016/j.jhazmat.2023.132529.

3. Press Release: The Endocrine Society. https://www.endocrine.org/news-and-advocacy/news-room/endo-annual-meeting/endo-2025-press-releases/chen-press-release