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The antibiotic actinomycin D blocks pregnancy in mice when administered as a single dose (15 μg) on the fourth day after mating (Finn & Martin, 1972). Experiments using ovariectomized pregnant mice, induced to implant with exogenous ovarian hormones and maintained on progesterone, showed that after the administration of the drug the early stages of implantation [the attachment of the trophoblast to the uterine epithelium (Pollard, Bredl & Finn, 1973), stromal oedema and increased vascular permeability (Finn & Bredl, 1973)] proceed normally but transformation of the stromal cells into decidual cells and degeneration of the uterine epithelium are delayed for about 30 h. A further finding was that the blastocysts, in spite of the drug, were stimulated to continue their development at the normal time. This was interesting because it suggested that whatever the nature of the stimulus given to the blastocyst at the time of implantation it was not dependent on
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SUMMARY
The decidual cell reaction (DCR) of ovariectomized mice treated with hormones and stimulated by the intrauterine injection of oil was investigated to obtain information about the control of uterine sensitivity during implantation. Three factors were studied; oestrogen given at the time of oestrus, progesterone and oestrogen given at the time of the nidatory surge.
For the induction of the DCR by oil both 'oestrous' oestrogen and 'nidatory surge' oestrogen were essential, whereas neither were necessary for the traumatic DCR. The quantity of nidatory surge oestrogen was very critical; 0·01 μg. were effective, 0·0625 μg. inhibitory. There was no quantitative interaction between nidatory surge oestrogen and progesterone, indicating that in this situation the two hormones are acting independently. The optimum time interval between initiating the oestrogen surge and injecting the oil was between 4 and 8 hr.
No response was obtained when the oestrogen surge was produced and the stimulus applied on the second day of treatment with progesterone; maximal responses were obtained on the fourth and fifth day and a reduced response on the seventh day. After an oestrogen surge on the fourth day, it was not possible to elicit an oil DCR to a further dose of oestrogen on the fifth day, indicating that the period of sensitivity induced by the surge on the fourth day is followed by a period of refractoriness.
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ABSTRACT
Ovariectomized mice were treated with oestrogen and progesterone on a schedule to mimic early pregnancy. Decidualization was induced with oil and uteri were examined at various times after the last progesterone injection.
The first morphological change detected in the uterus of decidualized mice following withdrawal of progesterone was infiltration of leucocytes into the stroma. This preceded overt tissue breakdown and extravasation of blood cells, and did not occur following withdrawal of progesterone without decidualization. It is suggested either that there is a release of a chemoattractant from decidual cells before any morphological changes are apparent or that the signal for attracting the leucocytes is released at the time of decidual induction, but that their migration is suppressed by progesterone.
J. Endocr. (1986) 110, 93–96
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ABSTRACT
Ovariectomized mice were prepared for decidualization with oestrogen and progesterone and arachis oil injected into the uterine lumen. Hormone injections were then stopped and uteri examined at intervals between 31 and 84 h after the last progesterone injection. At 31 and 35 h the stroma showed a normal decidual reaction. Between 45 and 79 h the stroma underwent a series of changes which started with the congestion of dilated blood vessels with swollen erythrocytes followed by breakdown of the vessel walls and extravasation of blood. At the same time the decidual cells showed typical apoptotic changes and there was invasion by leucocytes. An outer ring of stroma did not take part in the degenerative process and eventually a central core of blood cells and degenerating decidual cells became detached and was shed into the lumen.
Animals treated in exactly the same way but with the omission of the decidual stimulus did not show such changes in the stroma. It is suggested that the changes in the endometrium resemble those of menstruation and support the suggestion that for menstruation to occur the stroma must be differentiated for implantation. This occurs during the cycle in women but does not occur in non-primates unless a decidual stimulus is applied to the uterus.
J. Endocr. (1984) 100, 295–300
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SUMMARY
Uterine sensitivity and insensitivity to a decidual stimulus were induced in ovariectomized mice by daily treatment with progesterone and oestradiol. Uteri from these animals were examined with the electron microscope in an attempt to correlate ultrastructural changes with these states.
Progesterone alone brings the uterus to a state of 'presensitivity' and this is characterized by closure of the uterine lumen with interdigitation of microvilli from opposite luminal surfaces. This state can be held for long periods but when oestrogen is also given the uterus becomes sensitive for a short period and then insensitive. Morphologically the latter state is characterized by very close apposition of the luminal surfaces with the loss of the microvillous structure. This is referred to as the second stage of closure and is usually reached after 4 or 5 days of treatment with low sensitizing doses of oestradiol, but with higher doses, which induce insensitivity to a decidual stimulus, it is reached prematurely.
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Department of Physiology, Royal Veterinary College, Royal College Street, London, NW1 OTU, and *Imperial Cancer Research Fund, Lincolns Inn Fields, London, WC2A 3PX
(Received 8 June 1976)
Although the endometrial glands form a prominent part of the uterus of rodents, surprisingly little is known of the factors controlling their secretion, or indeed of the function of the secretion. During pregnancy the glands proliferate on the third day after mating in response to the high levels of oestrogen secreted during pro-oestrus (Finn & Martin, 1967, 1973). Secretion, however, does not become apparent in the lumina of the glands until day 6 of pregnancy. The extent of secretion is difficult to quantitate because it is not possible to collect it. However histological sections, especially after staining with the periodic acid-Schiff's (PAS) technique, reveal clearly the presence of a mucopolysaccharide substance in the lumina of the glands so that an approximate subjective assessment
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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.
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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.
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SUMMARY
Actinomycin D can induce a small number of implantations in pregnant mice undergoing progestin-induced delayed implantation following ovariectomy. However, the response of the uterus to the blastocyst is considerably retarded compared with the response observed when implantation is precipitated by oestradiol.
With the electron microscope the attachment reaction between the trophoblast and uterine epithelium is evident about 48 h after administration of the drug. However, the differentiation of the luminal surface of the epithelial cells in areas of uterus distant from a blastocyst (2nd stage of closure), which normally accompanies implantation, and can be induced by oestradiol in progesterone-treated animals, is not seen. Thus actinomycin D, although allowing implantation to proceed, does not completely mimic the actions of oestradiol on the progesterone-treated uterus.
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SUMMARY
During the preparation of the uterus for implantation of blastocysts the luminal surface of the epithelial cells undergoes a characteristic differentiation. In non-pregnant animals this can be induced by progesterone and oestrogen, but in pregnant animals the basic hormonal control is augmented by a local effect of the blastocyst. This has been demonstrated by examining the uteri of animals made unilaterally pregnant. The differentiation of the luminal epithelial surface of the fertile horn was in advance of that in the sterile horn. The injection of oil into one horn of the uterus of pseudopregnant animals also accelerated the change in the luminal surface of the injected horn.
It is suggested that contact with the cell membrane of the trophoblast influences differentiation of the uterine epithelium and that oil is able to mimic this contact reaction.
