Relationship of Serum Progesterone and Progesterone Metabolites with Mammographic Breast Density and Terminal Ductal Lobular Unit Involution among Women Undergoing Diagnostic Breast Biopsy

Manila Hada; Hannah Oh; Shaoqi Fan; Roni T Falk; Berta Geller; Pamela Vacek; Donald Weaver; John Shepherd; Jeff Wang; Bo Fan; Sally Herschorn; Louise A Brinton; Xia Xu; Mark E Sherman; Britton Trabert; Gretchen L Gierach

doi:10.3390/jcm9010245

Relationship of Serum Progesterone and Progesterone Metabolites with Mammographic Breast Density and Terminal Ductal Lobular Unit Involution among Women Undergoing Diagnostic Breast Biopsy

J Clin Med. 2020 Jan 17;9(1):245. doi: 10.3390/jcm9010245.

Authors

Manila Hada¹, Hannah Oh², Shaoqi Fan¹, Roni T Falk¹, Berta Geller³, Pamela Vacek⁴, Donald Weaver⁵, John Shepherd⁶, Jeff Wang⁷, Bo Fan⁸, Sally Herschorn⁹, Louise A Brinton¹, Xia Xu¹⁰, Mark E Sherman¹¹, Britton Trabert¹, Gretchen L Gierach¹

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Division of Health Policy and Management, College of Health Science, Korea University, Seoul 02841, Korea.
³ Department of Family Medicine, University of Vermont and Vermont Cancer Center, Burlington, VT 05401, USA.
⁴ Department of Medical Biostatistics, University of Vermont and Vermont Cancer Center, Burlington, VT 05401, USA.
⁵ Department of Pathology, University of Vermont and Vermont Cancer Center, Burlington, VT 05401, USA.
⁶ Population Sciences in the Pacific Program (Cancer Epidemiology), University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
⁷ Graduate School of Medicine, Hokkaido University, Sapporo 060-080, Japan.
⁸ Department of Radiology & Biomedical Imaging, University of California, San Francisco, CA 94115, USA.
⁹ Department of Radiology, University of Vermont and Vermont Cancer Center, Burlington, VT 05401, USA.
¹⁰ Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
¹¹ Mayo Clinic, Jacksonville, FL 32224, USA.

Abstract

The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40-65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.

Keywords: breast cancer; breast density; liquid chromatography-tandem mass spectrometry; mammographic density; progesterone; serum progesterone assay.