Endogenous progesterone metabolism in premenopausal women and subsequent breast cancer risk

The role of endogenous progesterone and its metabolites in breast cancer etiology among premenopausal women remains poorly defined. Prior studies have focused on postmenopausal women or progesterone measured in the luteal phase. We evaluated associations of circulating progesterone and related metabolites with subsequent breast cancer risk, accounting for menstrual cycle timing among premenopausal women at blood draw. We also evaluated associations with adrenal androgens and parent estrogens for comparison with prior studies. A case-cohort study was conducted within the Sister Study and the Cancer Prevention Study-3, including 1,696 premenopausal women not using exogenous hormones (676 incident invasive breast cancer cases and 1,020 subcohort participants) with stored serum samples (average age at blood draw, 43.3) and information on menstrual cycle phase of blood draw. Hormone levels were quantified by liquid chromatography-tandem mass spectrometry. Cox proportional hazards regression with robust variance adjustment for the case-cohort design was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with age as the time scale. Subcohort participants contributed person-time from baseline until diagnosis, death, or end of follow-up. Breast cancer cases not diagnosed within the subcohort contributed person-time to their risk set only. Models were stratified by study, to account for potential differences in baseline hazards, and adjusted for menstrual cycle phase at blood draw, body mass index, prior hormonal contraceptive use duration, age at last birth, and alcohol use. Women with higher circulating levels of pregnenolone (HR associated with a per standard deviation increase in circulating level: 1.15 [95% CI 1.01-1.31]) and 17-hydroxyprogesterone (1.12 [1.02-1.24]) were at increased risk for invasive breast cancer. HRs for progesterone and progesterone metabolites were as follows: progesterone 1.06 [0.98-1.14]; 5alpha-dihydroprogesterone 1.08 [0.98-1.19]; 3alpha-dihydroprogesterone 1.06 [0.95-1.17]; 20alpha-hydroprogesterone 1.02 [0.93-1.12]. Women with higher androgen concentrations, including androstenedione (1.19 [1.04-1.37]) and testosterone (1.22 [1.11-1.35]), were at increased risk for invasive breast cancer. The other measured androgens (dehydroepiandrosterone 1.06 [0.93-1.20]; dihydrotestosterone 1.04 [0.91-1.19]) and parent estrogens (estrone 1.02 [0.91-1.15]; estradiol 1.01 [0.91-1.12]) were not associated with risk. In this prospective study, higher concentrations of progesterone precursor, pregnenolone, progesterone metabolite, 17-hydroxyprogesterone, and androgens, androstenedione and testosterone, were associated with increased breast cancer risk. These findings support greater adrenal steroidogenic activity linked to increased breast cancer risk in premenopausal women.