Progesterone Exposure and Breast Cancer Risk—Addressing Barriers

Exposure to endogenous sex hormones has long been recognized as an important (albeit unavoidable) source of risk for cancer, particularly of reproductive organs. Studies addressing the breast cancer risk associated with endogenous hormone exposures have reported the increased breast cancer risk experienced by postmenopausal women who have higher than average serum levels of estradiol and its androgenic precursors. For example, in the European Prospective Investigation into Cancer and Nutrition cohort, the relative risk of breast cancer per doubling of serum estradiol in women sampled when postmenopausal was 1.31 (95% CI, 1.08-1.58).1 Of note, the European Prospective Investigation into Cancer and Nutrition investigators did not measure progesterone levels in postmenopausal women “as ovarian progesterone synthesis ceases after menopause.”1(p4183) The understudied possibility that progesterone exposure may be associated with breast cancer risk is highly relevant, particularly because efforts are under way to develop natural progesterone as a safe alternative to progestins in menopausal hormone therapy regimens.2 Although the major focus for more than 50 years has been on estrogens, progesterone and progestin exposure is increasingly recognized as instrumental in the breast cancer risk associated with exposure to the reproductive hormones. The evidence supporting an important promoting role for progesterone3 includes data regarding risk associated with increasing number of ovulatory cycles,4 and on high cell proliferation rates during the luteal phase of the menstrual phase.5 These and other data together suggest a specific protumorigenic role of progesterone, at least in the premenopausal breast. However, studies of endogenous progesterone exposure have faced both biological and technical barriers. In premenopausal women, research has been hampered by the cyclical variation of serum progesterone levels, so that even when studied, no clear trends emerge.1 In postmenopausal women, the extremely low concentrations of circulating progesterone renders it below the level of detection in studies using classical methods; and methods using liquid chromatography and mass spectrometry have not yet been widely applied. For these reasons, the data reported by Trabert and colleagues8 are of particular interest. Improvements in methods for measurement of hormones now allow questions regarding progesterone exposure to be addressed in postmenopausal women. Trabert et al8 used blood samples and data collected from the Breast and Bone Follow-up to the Fracture Intervention Trial, to perform a case-cohort analysis that included 405 incident breast cancer cases diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women not using exogenous hormones. They measured circulating concentrations of pregnenolone, progesterone, and their major metabolites, and used estradiol data measured for previous analyses of this cohort. They found progesterone concentrations displayed a mean (SD) of 4.6 (1.7) ng/dL. Higher circulating progesterone levels were associated with a modestly increased breast cancer risk, with a hazard ratio of 1.16 (95% CI, 1.00-1.35) per SD of serum progesterone. The association with progesterone was linear and stronger for 267 women with invasive breast cancers, where the hazard ratio was 1.24 (95% CI, 1.07-1.43; P = .004). Trabert et al8 also examined estradiol and progesterone together, and found that higher progesterone concentrations were associated with reduced breast cancer risk among women in the lowest quintile of circulating estradiol (<6.30 pg/mL). Here, they observed that the hazard ratio per SD was 0.38 (95% CI, 0.15-0.95); P = .04. Conversely, risk was increased among women in the second to fifth quintiles with estradiol greater than or equal to 6.30 pg/mL, where they found a hazard ratio of 1.18 (95% CI, 1.04-1.35) P = .01; P = .04 for interaction. + Related article