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UTERINE GLANDS, UTERINE MILK AND RECURRENT PREGNANCY LOSS By: AUTHOR: · Past President: FOGSI
INTRODUCTION: From the undergraduate days in medicine, one wonders, what is the role of the uterine glands in the endometrium? While the proliferative phase and the secretory phase differences are very basic to this teaching, what secretory function and its significance remain by and large unexplained paradigm for students of our subject. Latest developments in science have opened up the hitherto hidden facts of these glands. As expected they have a critical role to play in early pregnancy implantation and maintenance. Disruption of the secretory function can lead to defective implantation and growth. This can ultimately lead to miscarriage. Strangely enough, this disruption can occur again and again leading to recurrent pregnancy loss. This chapter examines the latest developments in the understanding of the vital events in the early days of pregnancy and subsequent obstetric bearing. FIRST FEW DAYS OF PLACENTATION AND RECURRENT PREGNANCY LOSS Human pregnancy is often called a two-stage pregnancy. By two-stage, it is meant that it is initially maintained by the corpus luteum and by 12 to 14 weeks the placenta takes over. This does not mean that the placentation process is not on till 12-14 weeks of human pregnancy. Not only is this process on, but it is very robust. It is laying a foundation for a very healthy obstetric outcome. Events taking place in early pregnancy can have effects as late as at term or just before that 1. Placental development in the human starts at the time of implantation at or around day 7 post-conception. By day 11 post-conception, the conceptus is already implanted within the shallow or superficial layers of endometrium. By the end of the subsequent week, placental villi cover the total surface of the gestational sac. The placental villi exhibit a bilayer epithelium consisting of cytotrophoblasts with overlaying syncytium (syncytiotrophoblasts). The trophoblasts with well-defined cell walls are called cytotrophoblasts. Soon at the tips, they merge leading to the dissolution of the cell walls. These are what called syncytiotrophoblasts. The shell of trophoblasts with syncytiotrophoblasts at the tip is very robust, vital and alive. It decides the fate of pregnancy in a big way. Events that are to happen after days, weeks or months in an ongoing pregnancy originate here. The shell with syncytiotrophoblasts at its tip remodels the spiral arterioles of the endometrium. This remodeling is a critical happening. It converts the spiral arterioles into the decidual arterioles. In the bargain, it shields off the vasculature from changes in the maternal systems thus making the fetoplacental unit autonomous, tightly controlled and self-regulatory 2. THE AUTONOMOUS TIGHT UNIT At this stage of early pregnancy, the autonomous fetomaternal unit does not need any nutrition from the mother nor does it need any extra protection from her. It is so brilliantly devised that it has to essentially function in a hypoxic environment thereby not needing even oxygen from the mother for its survival. As currently known to science, this tightness and autonomous ambiance are necessary as the all-important organogenesis is happening. At the same time, the fetus a foreign protein for the mother (and therefore amenable to rejection) is getting tolerated. The maternal system is learning to tolerate the conceptus. With such a critical phenomenon occurring, the fetal unit is kept tightly secured and protected. The mother has hardly any control or influence on this phase. UTERINE GLANDS AND PLACENTATION Right from the graduate days, students of the subject are taught about the structure and histopathology of the endometrium. While most teachers do this detailing very efficiently, but when it comes to explaining the function of different structures in the uterine endometrium they tend to be a little suboptimal. This is because science itself has not been able to reveal the details of the functions of the structures that constitute the endometrium. Some good quality research in recent years has revealed some mysteries of uterine glands and their functions. It has now been shown that the endometrial glands have a critical function of synthesizing, transporting and secreting the nutrition essential for the early conceptus. This has now been found in nearly all mammals. Studies on human conceptus have ethical constraints. As a result, many of the conclusions are drawn from other mammalian species like the mice and ewes. Fliant and Spencer describe the morphogenetic events common to the post-conception events in the uterus 3. These events include:
The evidence that uterine glands and their secretions are critical for supporting the early pregnancy, has come as recently as in last decade 4. Uterine Milk: In 1959 it was Needham who formally coined the term uterine milk for the secretions of uterine glands. It was because of the nourishment that these secretions provide to the early conceptus5. The human placenta is haemochorial placenta meaning it is a type of placenta in which the maternal blood is in direct contact with the chorion. Though haemochorial, in human placenta (vis-à-vis other mammals), fetal villi do no float uncovered in the maternal blood. They are surrounded by endometrial (decidual) cells that secrete a fluid which nourishes the conceptus and therefore called uterine milk. This was stated as early as in 1884 by Von Hoffman6. It now appears that the influence of uterine milk is not confined to the nutrition of the conceptus but also influences healthy implantation. Understandably, therefore, problems in this process can cause recurrent pregnancy loss and infertility. Having introduced the term uterine milk, one more term needs an introduction - histotrophs. The term histotroph means the total of all nutrient material derived from maternal tissues other than from her blood and is utilized by the embryo for its survival and nourishment. Histotrophy originally indicated the additional nourishment that the embryo receives beyond that from the maternal blood. But scientific research has proved that in early human pregnancy it is not the additional nutrition but the only and critical nutrition that the conceptus receives. Hematogenous source of maternal nutrition becomes accessible only at and after twelve to fourteen weeks. Among eutherian mammals including humans, two principal pathways have evolved to transfer nutrients from the mother to her fetus. These are termed histiotrophic and hemotrophic, respectively7. Histiotroph is an extracellular material derived from the endometrium and the uterine glands that accumulate in the space between the maternal and fetal tissues. It is phagocytosed initially by the trophectoderm of the blastocyst, and later by the trophoblast of the placenta or the endoderm of the yolk sac. By contrast, hemotrophic nutrition is the exchange of blood-borne materials between the maternal and fetal circulations. This is facilitated by the extensive and intimate apposition of the maternal and fetal tissues that occurs within the placenta. Before implantation, nutrition of the mammalian conceptus is therefore essentially histiotrophic. Once the placenta is established, hemotrophic nutrition becomes predominant, although the two pathways may coexist for much of gestation in certain species7. Some interesting studies have cast doubt upon the ability of the hemotrophic pathway to meet the energy and elemental requirements of the fetus during the first trimester of pregnancy8 9. Uterine milk also contains carbohydrates and lipids besides amino acids. The three together provide a rich source of energy needed to support the rapid proliferation of cells. Uterine milk also contains a variety of growth factors that stimulate the proliferation and growth activity of the trophoblasts. UGKO Cells: Uterine Gland Knockout (UGKO) epithelial cells as the term signify has proved to be very useful in the understanding of the fetoplacental unit in early pregnancy. The term UGKO has come from experiments in the pregnant ewes. It has been found that the epithelial cells and their secretory activities can be efficiently blocked by progestins. The hypothesis that progestins can block the uterine glandular activity was tested by Bartol et al in 1988 10. They exposed ewes to norgestimate, a potent synthetic progestin, from their birth to postnatal day 13 and found that the uterine adenogenesis was successfully inhibited. Exposure of the neonatal ewes to norgestimate did not hamper the gross development of Mϋllerian system in this study. It also did not affect the development of the brain or the hypotahalamo-pituitary-ovarian axis. But it decisively blocked the development of the glandular component in the endometrium. This resulted in infertility or subsequent miscarriages in the ewes. It decidedly proved the role of the glandular component of the endometrium in successful nidation and healthy continuation of pregnancy. Results from these studies explained the critical role of uterine glands in the secretion of uterine milk and subsequent healthy pregnancy outcome.
Most of the contents of uterine milk are nutritive amino acids. They also have other developmental functions. It includes stepwise development of the early embryo as well as the migration of primitive structures to right positions like the trophectoderm. Any disturbance in this can disrupt the milieu, resulting in early pregnancy loss. It is also possible that adverse functioning of these pregnancy supporting structures can also produce its effects on the activity of the trophoblasts and can subsequently increase the possibility of preeclampsia. Thus, deficient glandular activity is hypothesized to be responsible for early pregnancy loss and other complications subsequently. With many of the above mechanisms having their basis in animal experiments, one would always like to know if such a mechanism operates in humans also. Circumstantial evidence strongly indicates it to be indeed a possibility. This is particularly true for a very interesting phenomenon of blastocyst-decidual crosstalk. The Crosstalk:
The maternal circulation in and through the placental bed is established towards the end of the first trimester (about 11-13 weeks of pregnancy). Till then the nutrition of the conceptus is maintained through endometrial glands, as stated. These secretions are produced, transported and delivered into the cavity of the placenta. The early and young villi are bathed in these secretions so also are the trophoblasts. One question that can arise at this stage is – what maintains the supply of the trophoblasts. The answer to this is also very interesting. Trophoblasts send signals to the endometrial glands and upregulate growth factors. This is a function of the blastocyst-endometrial crosstalk. These growth factors include epidermal growth factors (EGF), Fibroblast Growth Factor-2 (FGF2) and Insulin-Like Growth Factor-1 (IGF1). In bovine experimental studies, cooperative interactions for EGF, FGF2, and IGF1 on the proliferation of the bovine trophoblast cell line and resultant bovine embryo development has been clearly shown 17. All these factors are in-turn required for the trophoblast stem cells. These stem cells are the source for the supply of trophoblasts. This concept of crosstalk came originally from animal experiments. Circumstantial evidence suggests that this may indeed be the case. The endometrial gland cells display the same array of endocrine receptors as are expressed in animal species, and pathologists have long recognized the hypersecretory phenotype that the glands adopt in early pregnancy, the so-called Arias-Stella reaction. Lower levels of glycoproteins secreted by the glands, such as glycodelin-A, have been linked to miscarriage when it is known that in 70% of cases formation of the trophoblastic shell is incomplete 2. Furthermore, microarray analysis of chorionic villus samples from patients that went on to develop pre-eclampsia show aberrant expression of decidual, rather than placental, genes 18. It is indeed possible that the defective dialogue leads to defective placentation and subsequently to the development of preeclampsia.
REFERENCES 1.
Matthiesen L, Berg G, Ernerudh J, Ekerfelt C, Jonsson Y,
Sharma S Immunology of preeclampsia. Chem Immunol Allergy.
2005; 89:49-61. |
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