Estrogens and Their Genotoxic Metabolites Are Increased in Obese Prepubertal Girls

Context:Estrogen levels and their metabolites are higher in obese vs lean postmenopausal women, and obesity increases breast cancer risk. Quinone derivatives of 4-hydroxylated estrogen metabolites, independently of the estrogen receptor, cause depurination and impaired DNA repair (genotoxic). 16α-Hydroxy (16α-OH)-estrone (E1), eg, promotes tumor proliferation and 2-methoxy-estradiol (E2) may be chemoprotective. Childhood obesity increases breast cancer death risk in women, but levels of estrogen derivatives had not been previously studied in young children.Objective:The objective of the study was to investigate whether total and genotoxic estrogens are increased in prepubertal obese girls compared with lean controls.Design:Stored sera from 12 lean and 23 obese prepubertal girls (Tanner stage I breast and pubic hair) studied previously were assayed for E1, E2, and their multiple metabolites (12 steroids total) using highly sensitive liquid chromatography and tandem mass spectrometry.Results:E2concentrations were significantly higher in obese [3.45 (0.5, 4.65) pg/ml (median [quartile 1, quartile 3])] vs lean girls [0.5 (0.5, 2.37), P= .04], 57% of values upper quartile or greater (quartile 3) of controls. Concentrations of 16α-OH-E1were higher in obese [7.17 (0.5, 9.64) pg/mL] vs lean girls [0.5 (0.5, 1.72, P= .007)], 65% of values quartile 3 or greater of controls. 2-Methoxy-E2concentrations were lower in the obese group (P= .012). 16α-OH-E1concentrations were positively correlated with body mass index, percentage fat mass, and IL-6 concentrations (P< .001).Conclusions:E2and genotoxic metabolites were higher in obese vs lean prepubertal girls. These data suggest that obesity is associated with an increased extraglandular estrogen production and metabolism before the onset of puberty in girls. Long-term epidemiological studies are needed to assess any potential increase in breast cancer risk.