Abstract
The role of endogenous progesterone in the development of breast cancer remains largely unexplored to date, primarily owing to assay sensitivity limitations and low progesterone concentrations in postmenopausal women. Recently identified progesterone metabolites may provide insights as experimental data suggest that 5α-dihydroprogesterone (5αP) concentrations reflect cancer-promoting properties and 3α-dihydroprogesterone (3αHP) concentrations reflect cancer-inhibiting properties. To evaluate the association between circulating progesterone and progesterone metabolite levels and breast cancer risk. Using a sensitive liquid chromatography-tandem mass spectrometry assay, prediagnostic serum levels of progesterone and progesterone metabolites were quantified in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (n = 15 595). Participation was limited to women not receiving exogenous hormone therapy at the time of blood sampling (1992-1993). Incident breast cancer cases (n = 405) were diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within 10-year age and clinical center strata. Progesterone assays were completed in July 2017; subsequent data analyses were conducted between July 15, 2017, and December 20, 2018. Circulating concentrations of pregnenolone, progesterone, and their major metabolites. Development of breast cancer, with hazard ratios (HRs) and 95% CIs was estimated using Cox proportional hazards regression adjusted for key confounders, including estradiol. Evaluation of hormone ratios and effect modification were planned a priori. The present study included 405 incident breast cancer cases and a subcohort of 495 postmenopausal women; the mean (SD) age at the time of the blood draw was 67.2 (6.2) years. Progesterone concentrations were a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Among women in the lowest quintile (Q1) of circulating estradiol (<6.30 pg/mL) elevated progesterone concentrations were associated with reduced breast cancer risk per SD increase in progesterone levels (HR, 0.38; 95% CI, 0.15-0.95; P = .04) and increased risk among women in higher quintiles of estradiol (Q2-Q5; ≥6.30 pg/mL) (HR, 1.18; 95% CI, 1.04-1.35; P = .01; P = .04 for interaction). In this case-cohort study of postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer. Additional research should be undertaken to assess how postmenopausal breast cancer risk is associated with both endogenous progesterone and progesterone metabolites and their interactions with estradiol.
Highlights
It is well accepted that pharmacologic and physiologic concentrations of estradiol are associated with increased mitogenic activity of breast epithelial cells, the possible association with progesterone and breast cancer risk continues to be debated.[1,2,3,4,5,6,7] Studies reporting increased breast cancer risk with menopausal hormone therapy use have primarily evaluated exogenous synthetic progestogen use,[8,9,10] rather than endogenous progesterone
Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048)
The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004)
Summary
It is well accepted that pharmacologic and physiologic concentrations of estradiol are associated with increased mitogenic activity of breast epithelial cells, the possible association with progesterone and breast cancer risk continues to be debated.[1,2,3,4,5,6,7] Studies reporting increased breast cancer risk with menopausal hormone therapy use have primarily evaluated exogenous synthetic progestogen (progestin) use,[8,9,10] rather than endogenous progesterone. In addition to possible progestational effects, the progestins used in these menopausal hormone therapy formulations can have antiandrogenic, proandrogenic, glucocorticoid concentration, and antimineralocorticoid effects[11,12] and are unlikely to provide direct evidence as to the potential association between endogenous progesterone and breast cancer risk. Mechanistic studies using cell culture, tissue culture, and preclinical models have associated progesterone with the development of breast cancer.[13] To our knowledge, epidemiologic data are limited to 1 study reporting a null association between circulating progesterone levels and breast cancer risk among postmenopausal women.[14] This study was limited by assay technology, with almost 30% of samples having undetectable levels of progesterone. The association of the presence of endogenous progesterone with breast cancer risk among postmenopausal women has been infrequently studied primarily owing to low levels of circulating progesterone, inadequate sensitivity of available assays,[15] and/or large sample volumes required for clinical assays
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