Circulating sex hormones and volumetric breast density: A prospective study in women from the EPIC Florence cohort

Mammographic breast density (MBD) is a known risk factor for breast cancer. This study aimed to evaluate prospectively how circulating levels of sex hormones and sex hormones binding globulin (SHBG) are associated with volumetric percent density (VPD, %) and absolute breast dense volume (DV, cm³) measured after an average 13.5 years of follow up. We included 422 post- and 445 pre-menopausal women enrolled in the Florence section of the European Prospective Investigation into Cancer and Nutrition study. Blood levels of circulating sex hormones and SHBG were determined in serum samples collected at enrollment. The automated Volpara™ density software was used to obtain DV and VPD measures from the first available full-field digital mammography performed after enrollment. We carried out adjusted linear regression models for post-menopausal and pre-menopausal women, separately. Higher baseline blood levels of SHBG were associated with higher VPD both in post-menopausal (%Diff 17.2 III vs. I tertile, p-value 0.02, p-trend 0.02) and pre-menopausal women (%Diff 21.1 III vs. I tertile, p-value 0.004, p-trend 0.004). Among pre-menopausal women a modifying effect of parity emerged, with significant inverse associations of estradiol, free estradiol, estrone, and free testosterone with VPD in women with a lower number of births or higher age at every birth. DV was not associated with sex hormones or SHBG. A direct association between increasing serum level of SHBG and VPD was observed both in post- and pre-menopausal women. This association need to be further investigated in order to better understand the underlying mechanisms.