Endometrial function

Details Endometrial function Endometrial function

1997-09-18

2002-10-29

Wilson, Michael C. (Department: 1632)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C424S093100

Reexamination Certificate

active

06472374

ABSTRACT:

FIELD OF THE INVENTION
This invention relates, inter alia, to a method of altering one or more characteristics of mammalian endometrial tissue.
BACKGROUND OF THE INVENTION
Endometrial Physiology
Two major events are required for the embryo to become established in the mammalian uterus: firstly, the preparation of the endometrium so that it is receptive to the presence of a blastocyst which can then implant and acquire nutritive support through the formation of the placenta; and secondly, the modification of myometrial activity which must become quiescent and thereby allow the blastocyst to become resident within the uterine cavity without the danger of expulsion. Both these events are controlled by the action of the hormones of pregnancy, of which oestrogens and progesterone are particularly important. These steroid hormones act on the endometrium and myometrium through their receptors which are located in the nucleus of target cells. Once activated, the steroid-nuclear receptor complex interacts with specific regions within the DNA to stimulate, repress or de-repress genes that code for proteins and polypeptides such as enzymes or growth factors.
The initiation of implantation is brought about by a cascade of biochemical and biophysical changes. Adhesion molecules (e.g. CAM 105) have been implicated in the early stages of attachment of the blastocyst to the wall of the uterus. Afterwards, the blastocyst and endometrium adopt various stratagems to improve intimacy between fetal and maternal tissues. In ungulates, trophoblast cells which form the outermost layer of the blastocyst migrate into the uterine epithelium with which they subsequently fuse. Cell migration is carried a step further in women because it is not only isolated or specific cell types that migrate but large areas of trophoblast which insinuate between the uterine epithelial cells. In order to do this, some of the trophoblast cells fuse together to form a syncytium. The process is very rapid and the embryo becomes established in the uterine tissues without much apparent degeneration in the uterine epithelium. In some species the process of implantation is delayed, either to await environmental cues which ensure the young are born at favourable times of the year, or by physiological factors such as lactation so that the mother has finished weaning the previous litter before the next pregnancy becomes fully established.
The preparation of the uterus for implantation is regulated by the secretion of ovarian hormones. The transport of the fertilised egg through the oviduct has to be precisely timed so that it arrives in the uterus at the correct time of development and when the uterus is in a fit condition to receive it. Under most conditions the uterus is hostile to the embryo, more hostile in fact than some other areas of the body. The epithelial lining of the uterus is, under most conditions, resistant to attachment and invasion by trophoblast and it is only under very precise hormonal states that this resistance is relaxed.
In mice and rats unmated animals do not have a full oestrous cycle because they do not form a normal secretory corpus luteum which produces increasing amounts of progesterone. If mating occurs at oestrus, a time when high levels of oestrogens are secreted by the ovarian follicle from which the ovum is shed, a corpus luteum will form in the place of the ruptured follicle, rising concentrations of progesterone are then secreted, implantation occurs and pregnancy progresses (length, 21 days). If an infertile mating occurs, similar events occur except that the corpus luteum only lasts about 11 days and pseudopregnancy is curtailed.
The cellular and biochemical changes that take place in the endometrium have been most thoroughly studied in the mouse and the rat, though information about these aspects in women has increased substantially in recent years. The endometrium in all species is made up of three main tissues—luminal epithelium, glandular epithelium and stroma. Cell proliferation occurs at different times in the three tissues. Luminal cells proliferate just before oestrus (proestrus) under the influence of the rising levels of oestrogens produced by the follicles in the ovary. By day 1 of pregnancy (day of copulation plug in rodents) they have ceased division but then undergo a second, though smaller, burst of activity on day 3. Glandular cells show most activity on day 4 and then decline. Stromal cells do not proliferate until day 4 but thereafter, under the influence of progesterone, they reach high levels of proliferation by day 5. In women, less is known of these changes which presage the process of implantation but there appears to be peak proliferation in epithelial cells during the follicular phase of the cycle and in stromal cells during the luteal or secretory phase, as in the mouse and rat.
The purpose of endometrial cellular proliferation is not fully resolved. It is believed to prepare the endometrium for implantation by increasing the number of cells that will serve a nutritive and secretory function (glandular epithelium) and that participate in the very early stages of placentation (decidualization). As a prerequisite of successful implantation, cell mitosis may progress towards cellular differentiation and therefore plays a crucial role in the early events of the establishment of pregnancy. Evidence in support of this role is the endometrial production of growth factors (mitogens), cytokines and nuclear oncogenes. Many of these compounds are produced in increased concentrations in response to ovarian hormones acting through their receptors.
Amongst growth factors, much attention is currently given to epidermal growth factor (EGF), heparin binding epidermal growth factor (HBEGF), amphiregulin and insulin-binding growth factors (IGF-I and IGF-II). Evidence for the importance of the local (paracrine) action of at least one of these growth factors, amphiregulin, has been provided by recent experiments in mice. Inhibition of the implantation-specific and progesterone-regulated gene for amphiregulin was achieved by the anti-progestin, RU486, and this resulted in the prevention of implantation (Das et al. Molecular Endocrinology 9, 691-705, 1995).
Amongst the cytokines, leukaemia inhibitory factor (LIF) and colony-stimulating factor (CSF), which are also produced by the mouse uterus at the time of implantation, have been found from gene knockout studies to be indispensable, demonstrating that their removal is incompatible with implantation and normal placentation (Stewart et al. Nature 359, 76-79, 1992: Pollard et al. Developmental Biology 148, 273-283, 1991).
Amongst the nuclear oncogenes, levels of c-jun and c-fos (which are early indicators of gene transcription) increase in the uterus after oestrogen administration, and are inhibited by progesterone.
Important differences exist between various species in the extent of trophoblast invasion at the time of implantation. In women, the early trophoblast is highly invasive whereas in pigs, which have a non-invasive form of implantation, the endometrial epithelium is never breached throughout the three month gestation period. Failure of implantation in both these species is high, reaching about 60 and 30%, respectively. The reasons for this high rate of failure are complex and incompletely understood. In women, about half the loss is attributable to genetic abnormalities but in pigs, as in other ungulates where the loss is also high, genetic defects only account for a few percent of the total.
After implantation failure in women a fall in progesterone secretion causes bleeding, as at the end of the normal menstrual cycle; this does not occur in most other animals. Disorders of menstruation, as well as of implantation, are common. In addition menstrual bleeding, either as a consequence of sequential hormonal therapy, or in conjunction with continuous combined hormone replacement therapy or progestin-only long-acting contraceptives, is a significant cause of ill-health in women. The underlying reasons for this bleeding are the focus o

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