Effects of progestogens on the postmenopausal breast

Abstract

The potential for an increased risk of breast cancer linked to the use of synthetic progestins combined with oral estrogens is one of the main putative reasons for discouraging postmenopausal women fromusing any type of hormone replacement therapy (HRT) for more than a few years. Because no definitive proof exists, the available epidemiological results can be interpreted according to what seems biologicallyplausible to each investigator, including potential differences between various schedules of various steroids in various species and in vitro models.More than 60 years after the discovery ofprogesterone, the main effects of this endogenous steroid on the physiopathology of the breast during a normal luteal phase are still controversial. The lack of consensus on such basic knowledge concerningone of the most important targets of a natural ovarian hormone discovered in 1934 is amazing. In the most cited studies, nothing has been done to measure progesterone in plasma and to correlate the extremelydisparate cytological results with extremely erratic steroid levels at the time of surgical stress. In a recent study, with a better design, the physiological rise of endogenous progesterone during theluteal phase coincided with a drop in proliferation of breast epithelial cells, which appears to be only slightly delayed in comparison with what is described in the endometrium. Differences in doses andschedules of treatments with various synthetic progestins have largely contributed to the inconsistency in clinical recommendations. Based on the analysis of proliferation markers in surgical biopsies fromnormal human postmenopausal breast tissue, it is plausible that mitogenic activity is not identical during therapy with unopposed estrogens versus estrogens combined with progestogens, and is higher duringHRT that combines oral conjugated equine estrogens with medroxyprogesterone acetate than during HRT that combines transdermal estradiol and progesterone. It is misleading to put all progestogens in thesame bag irrespective of their chemical structure, and, more important, their effect may vary according to whether it is estrone or estradiol that is mainly accumulated in the breast tissue. The hypothesisof progesterone decreasing the proliferative effect of estradiol in the postmenopausal breast remains highly plausible.