Effects of sex steroids on proliferation in normal mammary tissue

Numerous women are treated with a combination of oestrogen and progestogen for contraception and hormone replacement therapy worldwide. A possible inc reased risk of cancer in target organs has been discussed vividly for many years. While oestrogens are clearly mitogenic for breast epithelial cells, there has been considerable uncertainty about the effects of progestogens. This article reviews current knowledge on this field, including our own dat a. Oestrogen receptors are down-regulated during the luteal phase, while pr ogesterone receptors remain at a high level throughout the menstrual cycle. According to most studies, irt vivo proliferation of normal breast epithel ial cells is higher during the luteal phase in the vast majority of women. Normal breast tissue can convert oestrone sulphate to oestradiol. A negativ e correlation between the levels of circulating oestradiol and the enzyme c onverting oestrone into oestradiol suggests a local regulatory mechanism of tissue oestradiol formation. Serum progesterone levels correlate positivel y with sulphatase activity while 19-norsteroid progestogens may be inhibito ry. We found that long-term continuous combined hormonal treatment with con jugated equine oestrogens and medroxyprogesterone acetate induced a prolife rative response in the breasts of surgically postmenopausal macaques. The e ffect of combined treatment was more pronounced than that of oestrogen trea tment alone. Both endogenous progesterone and exogenous progestogens increa se proliferation of breast epithelial cells. Exogenous progestogens down-re gulate both oestrogen and progesterone receptors. Oestrogen and progestogen s may have both direct and indirect stimulating effects on proliferation. T he finding of a positive correlation between insulin-like growth factor I m essenger RNA and proliferation found in hormonally treated women with low r eceptor levels suggests the possibility of nonreceptor-mediated effects of sex steroids on proliferation, which needs to be investigated further.