It is clear that progesterone is a natural anti-E, thus partially explaining its protective effect in endometrium. We showed this anti-estrogenic activity on BC in vitro, since R5020, a pure progestin, inhibited the E-induced growth of MCF7 cells (8). However, proposals concerning mechanism ofthis anti-estrogenic activity have varied with time: Induction of 17P-OH-steroid dehydrogenase (9), increase of inactive E-sulfates (20), down regulation ofthe ER, and inhibition of transcription of ERE-controlled genes by squelching of limiting receptor co-factors (21). The decrease in the ERa level in mammary glands, after progestin treatment of pre-menopausal women with a benign breast disease was demonstrated in a population of 67 women by two fine needle biopsies performed before and after a 20-30 days treatment with lynestrenol, i.e., a nor-testosterone progestin routinely used in France to treat benign breast disease in the 1980s. In the 20 women receiving only placebo, the ERa concentration measured by immunohistochemistry was not altered, while in the 47 women receiving lynestrenol, the ERa level was markedly reduced by this treatment in all patients (22). This finding was consistent with an anti-estrogenic action ofprogestin operating also in- vivo. Whether this effect will be good or bad in the long term remains controversial, since ERa" BC cells (both in-situ and invasive) are more aggressive than ERa+ BC cells (23). Moreover, while the ERa complex stimulates cell growth, it inhibits invasion of ovarian and breast cancer cells (24, 25). This is consistent with a possible better prognosis of BC in postmenopausal women taking HRT.
In other tissues, such as bone or endothelial vascular cells, the anti-E activity of systemic progestins is certainly not beneficial by inhibiting the favourable effects of Es. This might explain the increased incidence of stroke and coronary disease observed in the WHI trial when MPA was associated with E.
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