Progestin and breast cancer. The missing pieces of a puzzle.

The previous assumption that progestin does not promote breast cancer development needs to be re-examined since a growing body of evidence indicates the opposite. Data from recent experimental trials and results from clinical and epidemiological studies on hormonal contraceptives and hormone replacement therapy (HRT) have been confronted with breast cancer cases known from the German database of adverse drug reactions (ADR), reported in association with the use of progestin only contraceptives (POC) and combined oral contraceptives (COC). Also cases reported in association with HRT have been analysed. The available data complement one another showing a tumour promoting potential of progestin, possibly higher than that of a combination of estrogen and progestin. These assumptions are based on the following facts: 1) in estrogen-supplemented animals, progesterone has been shown to reactivate the growth of regressed tumour xenograft obtained from breast cancer cell lines, expressing both estrogen and progesterone receptor; 2) antiprogestin has been revealed to suppress the reactivation of the growth of tumour xenograft and to fully suppress the development of breast cancer in an animal model for BRCA1 gene mutation; 3) metabolites of progesterone have been recognised as potent regulators of cell proliferation, cell detachment and apoptosis; 4) progesterone has been shown to inhibit, in a dose-dependent manner, apoptosis in breast cancer cell lines and apoptosis induced by doxorubicin and 5-fluorouracyl (drugs used in breast cancer treatment); 5) an association between breast cancer and HRT was suspected upon the addition of progestin on a regular basis for the prevention of endometrial cancer; 6) in a randomised placebo-controlled trial on HRT an increased risk of breast cancer was shown for the combination of estrogen and progestin, but not for estrogen alone; 7) in epidemiological studies on POC the recognition of an increased breast cancer risk was most probably impeded due to previously unrecognised systematic selection bias; 8) in a large epidemiological study on the risk of early-onset breast cancer in association with COC an increased risk was detected for COC use up to 1975, but no increased, even a slightly decreased, risk was shown for users of low-dose COC, applied since 1976; 9) a considerably higher number of breast cancer cases have been reported from Germany on POC than on the widespread used COC [corrected] (111 versus 12); 10) the big resemblance among the breast cancers reported for POC and their similarity with breast malignancies diagnosed in pregnancy suggest the existence of a pattern rather than pure coincidence [corrected]