Urinary phthalate metabolites and central precocious puberty in girls: Evidence for luteinizing hormone mediation

• DEHP metabolites were positively correlated with LH in CPP cases. • Logistic models showed elevated, non-significant odds of CPP with DEHP exposure. • Mediation analysis revealed borderline indirect effects via LH. • BPA and cortisol showed no significant associations with hormone levels. • Findings suggest DEHP may influence puberty through endocrine disruption. There is growing concern that endocrine-disrupting chemicals (EDCs) may contribute to the rising incidence of central precocious puberty (CPP). This case-control study examined whether urinary concentrations of phthalate metabolites and bisphenol A (BPA) are associated with CPP risk. We recruited 77 girls (20 with idiopathic CPP and 57 age-matched controls) between 2021 and 2025 from a tertiary hospital in Saudi Arabia. Urinary EDCs were quantified using ultra-performance liquid chromatography–tandem mass spectrometry, and serum reproductive hormones, including luteinizing hormone (LH), follicle-stimulating hormone, estradiol, and cortisol, were assessed. Although urinary BPA and phthalate levels did not differ significantly between groups, LH correlated positively with several DEHP metabolites among CPP cases (rs = 0.34–0.45, p < 0.05). Specifically, di(2-ethylhexyl) phthalate (DEHP)-related metabolites—mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP)—were most consistently associated. Logistic regression suggested an increased risk trend for the molar sum of three DEHP metabolites (∑ 3 DEHP; OR = 2.18; 95% CI: 0.86–5.52) and the sum of high-molecular-weight (HMW) phthalates (∑HMW; OR = 1.91; 95% CI: 0.77–4.78), though not statistically significant. Cortisol levels did not differ between groups, but in CPP cases, moderate positive correlations were observed with MECPP and monobenzyl phthalate. BPA showed no significant associations with reproductive hormones or cortisol. Mediation analysis indicated borderline indirect effects via LH for several DEHP metabolites (MEOHP, MEHHP) and monobutyl phthalate (M n BP). Although M n BP showed the largest effect estimate, MEOHP was the most statistically suggestive (indirect effect = 0.79, p = 0.077). In conclusion, DEHP-related phthalates may influence early pubertal development through LH-mediated pathways. This study is novel in identifying LH as a potential mediator and detecting cortisol–phthalate correlations in CPP cases, underscoring the need for larger longitudinal cohorts with repeated biomonitoring to validate these findings.