The uteri of untreated ovariectomized mice consisted almost entirely of myometrium and connective tissue stroma. After oestrogenic stimulation these tissues underwent marked hypertrophy, but showed little proliferation.The luminal epithelium underwent marked hyperplasia, with most cells dividing twice to quadruple cell numbers by 35-40 h, when they made up 10-12% of the uterine tissue volume and 20% of the total uterine cell population. The proliferative response was rapid, highly synchronized and short-lived. The number of cells incorporating [3H]thymidine first increased 8\m=.\5h after oestradiol-17\g=b\ and by 13-16 h 60-70 % were engaged in DNA synthesis. Up to 21 h cell-death was minimal. From 21 h onwards the proliferation rate declined and the rate of cell death increased. A second injection of oestrogen prevented the rise in death rate and produced a second smaller burst of DNA synthesis. Cells in DNA synthesis or mitosis were insensitive to oestrogen.A smaller proliferative response occurred in the glands: only 25% of cells entered DNA synthesis after the first injection of oestradiol and none after the second. Gland cells appeared to die in situ and there was no evidence that they migrated into the luminal epithelium.

In order to study the changes taking place in the blastocyst and locally in the uterus at the site of the blastocyst attachment, pregnant mice were killed at intervals between 3 days 21 hr and 4 days 16 hr post coitum. The uteri were tested for the presence of Pontamine Blue areas (indicating increased permeability of capillaries) and histochemically for alkaline phosphatase in the stroma, and also examined histologically. By classifying each female for the various features studied, the following order of appearance was established : Pontamine Blue reactivity,`W \ x=r eq-\ bodies' emerging from blastocyst, local oedema of the uterine stroma, alkaline phosphatase in the uterine stroma, histological decidualization. Giant cell transformation of the trophoblast occurred at about the same time as the emergence of W-bodies from the blastocyst. Blastocyst elongation began after the appearance of Pontamine Blue reactivity and before histological decidualization, but was not sequentially related to the other features studied.

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Implantation involves the attachment of the blastocyst to the wall of the uterus with, in some cases, the embedding of the entire ovum in the uterine wall. Associated with it are very profound and characteristic changes in the endometrium both during preparation for implantation and following attachment of the blastocyst. In this chapter, the uterine changes that take place during preparation will be considered first and then the changes during the process of implantation. The former occur regularly and frequently throughout the life of most female mammals, whereas the latter are rarer events, especially in women. This division of the subject is also convenient for the consideration of the control mechanism involved. Whereas the preparative changes are largely directed by the varying levels of the hormones secreted by the ovary, once the implantation process has been initiated hormones playa largely permissive role.There is considerable species variation in the reaction of the uterus in preparation for and during implantation. De Feo (1967) reviewed this subject very thoroughly in the first edition of this book. The great majority of research investigations have been carried out on laboratory rodents, with very little on primates or the larger domestic animals. It follows therefore that any general account of implantation will lean heavily on information acquired from laboratory animals. Although one would like to have a much more general coverage, one cannot escape the reality that information acquired from many experiments on large numbers of laboratory animals provides a sound foundation on which to build. Information from primates or wild mammals will always tend to be fragmentary because of the difficulty of obtaining large numbers of specimens. Anyone who has worked with rats or mice knows how easy it is to be misled by the results from two or three animals. The only sensible course therefore is to get as

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.

The control mechanisms involved in implantation can be divided into those operating from outside the uterus and intracellular controls within the organ. The hormones of the ovary ensure that uterine preparation is synchronized with the presence of a mature blastocyst in the uterine lumen, whilst the intracellular controls regulate and integrate the changes which take place within the organ and between it and the blastocyst. A prominent feature of these changes in many species is the transformation of the connective tissue stromal cells into specialized decidual cells in which the blastocyst comes to lie, either by passing through the uterine epithelium or by degeneration of the epithelium around it. This transformation will be referred to as the decidual cell reaction (DCR). HORMONAL CONTROLIn the majority of animals implantation takes place at a fixed interval of time after ovulation (assuming a fertile copulation) when the corpus luteum is fully formed. This is during the luteal phase of the menstrual cycle or the dioestrous phase of the oestrous cycle. Implantation can thus be considered as the cul-

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Summary. Using a histochemical technique, alkaline phosphatase has been shown to appear in the stroma of the mouse uterus during implantation and after initiation of the oil-induced deciduoma.In sections of pregnant uteri the enzyme first appeared on the 5th day after mating as a small crescentic area in the stroma on the antimesometrial side of the uterus close to the implanting blastocyst.In pseudopregnant mice after instillation of oil into the uterine lumen (on the 4th day) a similar crescentic area of alkaline phosphatase activity appeared around the uterine lumen on the antimesometrial side on the 5th day.The epithelium in both cases is intact on the 5th day but degeneration occurs on the antimesometrial side on the 6th day. This suggests that epithelial degeneration is an inherent property of the uterus during the period of implantation, and is not directly caused by the activities of the giant cells of the trophoblast.There was no alkaline phosphatase activity in the uterine stroma of pseudopregnant untreated mice on the 4th, 5ht and 6th days after sterile mating and the epithelium showed no evidence of degeneration. Further, injection of oil into the uteri of ovariectomized mice failed to cause epithelial degeneration or result in alkaline phosphatase activity in the stroma.The bearing of these results on the role of the blastocyst in implantation is discussed.