Effect of High Intensity Sweeteners on the Reproductive System: From the Onset of Puberty to Menstrual Health: A Comprehensive Review of Human and Animal Evidence.

INTRODUCTION

High-Intensity Sweeteners (HISs) are widely consumed as calorie-free sugar substitutes, particularly among girls and women of reproductive age. Despite their regulatory approval, growing evidence suggests potential endocrine-disrupting properties that may negatively impact women's reproductive health.

OBJECTIVE

This narrative review synthesizes human and animal evidence on the Potential Pathological Effects of AS on puberty onset and menstrual health, while elucidating the underlying biological mechanisms.

METHODS

A structured search of references in PubMed, Scopus, Web of Science, and Embase up to 2025 was conducted, prioritizing studies from 2015 onwards. Inclusion criteria required quantitative measurements of AS exposure and reproductive endpoints in non-pregnant, non-lactating women, or relevant animal models. Seventeen studies (12 animals, 5 humans) were thematically synthesized.

RESULTS

Chronic exposure to AS specifically aspartame, sucralose, saccharin, and acesulfame-K-disrupts female reproductive physiology through composition-dependent and developmentally timed mechanisms. These mechanisms include (1) suppression of the hypothalamic-pituitary-gonadal (HPG) axis through downregulation of Kiss1; (2) ovarian mitochondrial dysfunction, oxidative stress, and follicular atresia; and (3) reduced estrogen production by the gut microbiota through disruption of the estrobulum. Importantly, these effects often occur independently of body weight or metabolic changes. Human data have linked maternal and prepubescent AS consumption to premature thelarche, menstrual irregularities, and altered rate of puberty, particularly in carriers of TAS1R2/TAS1R3 polymorphisms. It is noteworthy that not all sweeteners pose the same risk: advantame and glycyrrhizin show neutral or protective profiles.

CONCLUSION

Artificial sweeteners may not be harmless, especially above the acceptable daily intake (ADI), and they could act as bioactive endocrine disruptors. However, given that much of the current evidence derives from animal studies and limited observational human data, further well-designed human studies are needed to confirm these associations and clarify their clinical significance.