Increases in serum estrone sulfate level are associated with increased mammographic density during menopausal hormone therapy

Background: Menopausal hormone therapy increases mammographic density. We determined whether increases in serum estrone sulfate (EIS) levels during menopausal hormone therapy predict increased mammographic density. Methods: We measured percent mammographic density and serum E1S levels in 428 participants of the Postmenopausal Estrogen/Progestin Interventions study who were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg alone, CEE + daily medroxyprogesterone acetate (MPA) 2.5 mg, CEE + cyclical MPA (10 mg days 1-12 per 28-day cycle), or CEE + cyclical micronized progesterone (10 mg days 1-12). Serum EIS levels were determined by RIA. Information about covariates was determined by annual questionnaire. Using linear regression, we determined the association between change in E1S level from baseline to 12 months and change in percent mammographic density (by semiquantitative interactive threshold method). Results: After controlling for baseline mammographic density, age, body mass index, alcohol intake, parity, smoking, ethnicity, physical activity, and age at first pregnancy, mammographic density increased by 1.3% for every 1 ng/mL increase in E1S level (P < 0.0001). The association between change in E1S level and change in mammographic density differed by treatment group (greater effect in CEE + cyclical MPA group versus CEE group; P = 0.05). After controlling for treatment group, change in the ratio of E1S to E-1 was also positively associated with change in mammographic density. Conclusions: Increases in serum E1S levels during menopausal hormone therapy are associated with increases in mammographic density. The relative contribution of E1S and El to stimulation of breast tissue awaits further elucidation.