Abstract
BACKGROUND: The age of thelarche in girls has declined globally. While earlier menarche has been linked to higher breast density - a known risk factor for breast cancer - the association between earlier thelarche and breast density remains unclear. METHODS: 114 Girls presenting with idiopathic central precocious puberty without medication (ICPP), early thelarche (ET), and normal age at thelarche (NT) were recruited from pediatric endocrine clinics of three hospitals during the year of 2020-2021 in Hefei, Anhui Province, China and were followed up for 3-5 years. Participants had their breast composition measured by MRI at 1-year post menarche. Fasting blood samples were collected at baseline and follow-up to measure of reproductive hormone concentrations. RESULTS: The ET group and ICPP group exhibited significantly higher percent fibroglandular volume (%FGV: 42.1%, 52.0% ) and fibroglandular volume (FGV: 183.3 cm(3), 237.0cm(3)) compared with the NT group (%FGV: 34.7%, FGV: 148.8cm(3)) . Serum estrogen levels at baseline and follow-up were elevated in the ET group relative to the NT group (52.1 vs. 40.7 pg/ml; 46.1 vs. 38.6 pg/ml), but did not differ significantly from the ICPP group (baseline: 54.6 vs. 52.1 pg/ml; follow-up: 48.9 vs. 46.1 pg/ml). Each 1-year earlier onset of thelarche was associated with a 7.8% increase in %FGV and a 35.7 cm³ increase in FGV. The combined hormonal pathway mediated the association between early puberty (age at thelarche < 9 years) and %FGV in this study, accounting for 28.7% (95% CI: 8.6% - 51.3%) of the total mediation effect. For the association between early puberty and FGV, baseline estradiol mediated 27.7% (95% CI: 11.8% - 44.8%), the pathway from baseline to follow-up estradiol mediated 13.6% (95% CI: 5.0% - 24.3%), and the combined hormonal pathway mediated 45.8% (95% CI: 18.1% - 68.0%). CONCLUSION: In this cohort study, earlier thelarche (even between 8.0 and 9.0 years) was associated with higher %FGV and FGV. Prolonged estrogen exposure may represent a modifiable mediator that could be targeted for breast cancer prevention strategies in girls with earlier puberty.