PROGESTERONE AND THE NORMAL BREAST

Conventional wisdom holds that the mechanisms by which estradiol and progesterone regulate the proliferation and differentiation of uterine epithelial cells, apply equally to the breast. This is probably inaccurate (Anderson et al., 1987, 1989; Going et al., 1988). In the uterus, estrogens are clearly mitogenic, and the addition of progesterone to the estrogenized endometrium leads to the appearance of a secretory pattern characterized by cells engaged in protein synthesis rather than cell division (Berliner and Gerschenson, 1976). That is, in the uterus, estradiol is a proliferative hormone; progesterone is a differentiating hormone. For this reason the unopposed actions of estradiol are considered to be tumorigenic in the uterus, while the risk of endometrial hyperplasia and cancer is lowered when estrogens are combined with progestins. In fact, the combined regimen may even be protective since a decrease in endometrial cancers has been reported in women prescribed combined estrogens and progestins, compared to women receiving no treatment (Henderson et al., 1988).

However, considerable evidence has now accrued to suggest that in the epithelium of the breast, progesterone has a different influence—that, like estradiol, progesterone in the breast has a strong proliferative effect. Studies in support of this come both from experimental models and from normally cycling women. The proliferation of normal mammary epithelium in virgin mice, and the lobular-alveolar development of mammary tissues in pregnant mice, both require progesterone (Imagawa et al., 1985; Haslam, 1988). A fundamental difference in the actions of estradiol and progesterone in the breast is that the latter stimulates DNA synthesis, not only in the epithelium of the terminal bud but also in the ductal epithelium (Bresciani, 1971). The stimulating effects of progesterone on the development of mammary gland buds can be inhibited by progesterone antagonists (Michna et al., 1991).

Data from normal human mammary cells have been more difficult to obtain and are often equivocal. Compared to the increase caused by estradiol treatment (11.3-fold), progesterone treatment only marginally (2.0-fold) increases the mitotic index of normal human breast ductal epithelium maintained in intact athymic nude mice (McManus and Welsch, 1984). In fact, Mauvais-Jarvis and colleagues (Gompel et al., 1986; Mauvais-Jarvis et al., 1986) concluded, using primary cultures of epithelial cells from normal human mammary glands, that while estradiol treatment stimulates growth, progestins inhibit growth. Their data are difficult to interpret however, since the experiments using estradiol were done with cells growing in minimally supplemented medium, whereas the progestin treatment studies were done with cells in optimally supplemented medium, and any progestin growth-



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