SUMMARY
Progesterone treatment significantly altered the response of the mouse uterus to oestradiol-17β. Oestradiol given alone produced many mitoses in the luminal and glandular epithelia but not in the connective tissue stroma. After treatment with progesterone this pattern was reversed and oestradiol produced many mitoses in the stroma but few in the epithelia. Production of stromal cell division was influenced by the dose of progesterone and by the period of treatment; a single day of treatment greatly reduced the numbers of epithelial mitoses produced by oestradiol but did not greatly increase stromal mitosis. At least 3 days' treatment was necessary for a maximal stromal response.
Doses of oestradiol sufficient to inhibit implantation and deciduomata production did not reverse the stromal response but did overcome, in part, the progestational suppression of epithelial mitosis, producing large numbers of mitoses in the luminal but not in the glandular epithelium.
SUMMARY
Estimates were made of the number and distribution of cells undergoing division in the mouse uterus during the first 6 days of pregnancy. There was a spectacular change in the distribution of mitoses between days 3 and 4. On day 3 large numbers of mitoses were present in the luminal and glandular epithelium, with few in the stroma, whereas on days 4 and 5 very large numbers were present in the stroma with few in the epithelia.
On day 6 and late on day 5, in the vicinity of a blastocyst, the area containing decidual cells was free of mitoses. Many mitoses were found in the stroma immediately outside this area and there was evidence that the rate of division here was greater than in segments of the uterus unstimulated by a blastocyst.
It has been suggested that oestriol protects against breast cancer, because in some experiments on uterine growth it is only weakly active, and partially inhibits the effects of oestradiol-17beta. When its effects are measured 24 h after a single injection, oestriol behaves as a typical impeded oestrogen with low potency and a flat dose-response line. This does not result from failure to stimulate certain critical stages of growth but from failure to sustain the products of growth. We found that oestriol induced all phases of uterine growth including DNA synthesis and cell division. It was as effective as oestradiol in stimulating early increases in protein synthesis and uterine weight, and half as effective in stimulating epithelial cells to replicate DNA and divide. However, epithelial cell numbers did not increase after a single injection of oestriol because cell death rate increased at the same time as mitotic rate, apparently as a result of the more rapid loss of oestriol from the uterus. Repeated injections of oestriol prevented premature cell death and produced as much uterine hypertrophy and hyperplasia as oestradiol-17beta. These results support the thesis that the oestrogenic potency of a substance is largely determined by the duration of its occupation of receptors. Thus in situations of continuous production, (e.g. pregnancy) oestriol would be as active as oestradiol and unlikely to exert any significant 'buffering' or protective action. The findings are also discussed in relation to a new model for the regulation of cell proliferation.
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