Secondary oxidized di-2-ethylhexyl phthalate metabolites may be associated with progression from isolated premature thelarche to central precocious or early puberty

Phthalate esters (PAEs) may act as estrogen receptor agonists, and their relationship with precocious puberty is a global health concern. However, their role in isolated premature thelarche (IPT) progression remains unclear. We conducted a cohort study investigating the relationship between IPT progression and urinary PAE metabolites. Girls with IPT aged 6–8 years were regularly followed up every three months for one year. Clinical data and urine PAE metabolite levels were collected. Participants who progressed to central precocious puberty (CPP) or early puberty (EP) had significantly higher ovarian volume, breast Tanner stage, and levels of the creatinine-adjusted urinary secondary oxidized di-2-ethylhexyl phthalate (DEHP) metabolites (Σ(4)DEHP). Breast Tanner stage (odds ratio [OR] = 7.041, p = 0.010), ovarian volume (OR = 3.603, p = 0.019), and Σ(4)DEHP (OR = 1.020, p = 0.005) were independent risk factors for IPT progression. For each 10 µg/g/Cr increase in the urine level of Σ(4)DEHP, the risk of progression from IPT to CPP/EP within one year increased by 20%. This study demonstrated that the breast Tanner stage, ovarian volume, and Σ(4)DEHP in urine were independent risk factors for IPT progression, and Σ(4)DEHP may be associated with the progression of IPT to CPP or EP.