Background Steroid hormones influence breast morphology and cellular proliferation and are associated with breast carcinogenesis. However, their associations with mammographic breast density (MBD) are less studied, particularly in premenopausal women. We, therefore, investigated the associations of steroid hormone metabolites with MBD in premenopausal women. Methods Our study included 700 premenopausal women scheduled for screening mammograms. We analyzed 54 steroid hormone metabolites (Metabolon®) and assessed volumetric measures of MBD including volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV) using Volpara. We investigated associations using linear regression modeling to estimate the covariate-adjusted means of VPD, NDV, and DV, corresponding to each steroid hormone metabolite tertile and on a continuous scale. Models were adjusted for age, body fat percentage, age at menarche, race, alcohol consumption, family history of breast cancer, oral contraceptive use, body shape at age 10, and parity/age at first birth. We applied false discovery rate (FDR) to control multiple testing and determined significance at FDR-adjusted p-value ≤ 0.05. Results One corticosteroid (cortolone glucuronide (1)) and four androgenic steroid metabolites (androstenediol (3beta,17beta) monosulfate (2), androstenediol (3beta,17beta) disulfate (1), 5alpha-androstan-3alpha,17beta-diol monosulfate (2), and 5alpha-androstan-3alpha,17beta-diol disulfate) were inversely associated with VPD. For instance, VPD was lower monotonically across tertiles (T) of cortolone glucuronide (1) (T1 = 8.9%, T2 = 8.3%, and T3 = 7.3%; p-trend=7.55 × 10−5, FDR p-value = 0.01); androstenediol (3beta,17beta) monosulfate (2), (T1 = 8.8%, T2 = 8.6% and T3 = 7.5%; p-trend=8.89 × 10−4, FDR p-value = 0.03), and androstenediol (3beta,17beta) disulfate (1) (T1 = 9.0%, T2 = 8.4% and T3 = 7.6%; p-trend=8.41 × 10−4, FDR p-value = 0.03). Five progestin steroid metabolites were positively associated with VPD, but only 5alpha-pregnan-3beta,20alpha-diol monosulfate (2) was marginally significant after FDR correction (T1 = 7.5%, T2 = 8.2%, T3 = 8.8%; p-trend=4.56 × 10−3, FDR p-value = 0.06). Two corticosteroid metabolites, tetrahydrocortisol glucuronide and cortolone glucuronide (1), were positively associated with NDV. For instance, NDV was higher across tertiles of cortolone glucuronide (1) (T1 = 744.3 cm3, T2 = 829.0 cm3, and T3 = 931.8 cm3; p-trend=4.64 × 10−6, FDR p-value = 7.51 × 10−4). No metabolites were associated with DV. Conclusion We identified novel inverse associations of cortolone glucuronide (1) and four androgenic steroid metabolites with VPD, underscoring the importance of steroid hormone metabolites in MBD and the potential for modulating these in reducing MBD.

Steroid hormone metabolites and mammographic breast density in premenopausal women

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2025年11月3日

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Ghazaleh Pourali,
Kayode A. Matthew,
Myung Sik Jeon,
Chongliang Luo,
Gary J. Patti,
Jingqin Luo,
Adetunji T. Toriola

摘要

Background

Steroid hormones influence breast morphology and cellular proliferation and are associated with breast carcinogenesis. However, their associations with mammographic breast density (MBD) are less studied, particularly in premenopausal women. We, therefore, investigated the associations of steroid hormone metabolites with MBD in premenopausal women.

Methods

Our study included 700 premenopausal women scheduled for screening mammograms. We analyzed 54 steroid hormone metabolites (Metabolon®) and assessed volumetric measures of MBD including volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV) using Volpara. We investigated associations using linear regression modeling to estimate the covariate-adjusted means of VPD, NDV, and DV, corresponding to each steroid hormone metabolite tertile and on a continuous scale. Models were adjusted for age, body fat percentage, age at menarche, race, alcohol consumption, family history of breast cancer, oral contraceptive use, body shape at age 10, and parity/age at first birth. We applied false discovery rate (FDR) to control multiple testing and determined significance at FDR-adjusted p-value ≤ 0.05.

Results

One corticosteroid (cortolone glucuronide (1)) and four androgenic steroid metabolites (androstenediol (3beta,17beta) monosulfate (2), androstenediol (3beta,17beta) disulfate (1), 5alpha-androstan-3alpha,17beta-diol monosulfate (2), and 5alpha-androstan-3alpha,17beta-diol disulfate) were inversely associated with VPD. For instance, VPD was lower monotonically across tertiles (T) of cortolone glucuronide (1) (T1 = 8.9%, T2 = 8.3%, and T3 = 7.3%; p-trend=7.55 × 10⁻⁵, FDR p-value = 0.01); androstenediol (3beta,17beta) monosulfate (2), (T1 = 8.8%, T2 = 8.6% and T3 = 7.5%; p-trend=8.89 × 10⁻⁴, FDR p-value = 0.03), and androstenediol (3beta,17beta) disulfate (1) (T1 = 9.0%, T2 = 8.4% and T3 = 7.6%; p-trend=8.41 × 10⁻⁴, FDR p-value = 0.03). Five progestin steroid metabolites were positively associated with VPD, but only 5alpha-pregnan-3beta,20alpha-diol monosulfate (2) was marginally significant after FDR correction (T1 = 7.5%, T2 = 8.2%, T3 = 8.8%; p-trend=4.56 × 10⁻³, FDR p-value = 0.06). Two corticosteroid metabolites, tetrahydrocortisol glucuronide and cortolone glucuronide (1), were positively associated with NDV. For instance, NDV was higher across tertiles of cortolone glucuronide (1) (T1 = 744.3 cm³, T2 = 829.0 cm³, and T3 = 931.8 cm³; p-trend=4.64 × 10⁻⁶, FDR p-value = 7.51 × 10⁻⁴). No metabolites were associated with DV.

Conclusion

We identified novel inverse associations of cortolone glucuronide (1) and four androgenic steroid metabolites with VPD, underscoring the importance of steroid hormone metabolites in MBD and the potential for modulating these in reducing MBD.