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NCBI Bookshelf. Endotext [Internet]. TaylorMD. A coordinated sequence of events must occur in order to establish and successfully maintain a healthy pregnancy.
Synchrony between the development of the early embryo and establishment of a receptive endometrium is necessary to allow implantation and subsequent progression of pregnancy. The endocrinology of human pregnancy involves endocrine and metabolic changes that result from physiological alterations at the boundary between mother and fetus. Known as the feto-placental unit FPUthis interface is a major site of protein and steroid hormone production and secretion. Many of the endocrine and metabolic changes that occur during pregnancy can be directly attributed to hormonal als originating from the FPU.
The initiation and maintenance of pregnancy depends primarily on the interactions of neuronal and hormonal factors. Proper timing of these neuro-endocrine events within and between the placental, fetal, and maternal compartments is critical in directing fetal growth and development and in coordinating the timing of parturition. Maternal adaptations to hormonal changes that occur during pregnancy directly affect the development of the fetus and placenta.
Gestational adaptations that take place in pregnancy include establishment of a receptive endometrium; implantation and the maintenance of early pregnancy; modification of the maternal system in order to provide adequate nutritional support for the developing fetus; and preparation for parturition and subsequent lactation.
Known as the feto-placental unit FPUthis interface is a major site of protein and steroid hormone production and secretion Figure 1. Additionally, it serves as an endocrine, respiratory, alimentary, and excretory organ, facilitating the exchange of nutrients and metabolic products between the mother and fetus.
The fetus is dependent on this effective exchange with the mother for its proper intrauterine growth and development. Thus, it is not surprising that the fetus initiates and influences maternal adaptations to optimize this exchange via complex hormonal mechanisms. The interface between mother and fetus, known as the feto-placental unit FPUis a major site of protein and steroid hormone production and secretion. The menstrual cycle, involves a synchronous production of ovarian steroid hormones, estrogen and progesterone, which induces structural and functional changes within the endometrium in anticipation for embryo implantation and the establishment of a pregnancy.
During the luteal phase, under the primary influence of progesterone, the proliferative endometrium changes into secretory endometrium, which is well vascularized and composed of spiral arteries. A favorable environment for implantation is established via chemokines, growth factors, and cell adhesion molecules CAMs produced by the glandular secretory endometrium 1. The chemokines and CAMs serve to attract the blastocyst to the specific sites of implantation where the endometrium is strategically prepared for invasion and placentation 1.
When implantation does not occur, a timely regression and destruction of the fully developed endometrium le to menstruation. However, if implantation occurs, the endometrium continues to grow and undergoes further morphological and molecular changes to provide supportive environment for the growing embryo 2. Implantation has three stages: apposition, adhesion and penetration. Apposition is an initial unstable adhesion of the blastocyst to the endometrial surface. This stage is characterized histologically by the appearance of microprotrusions from the apical surface of the epithelium, termed pinopodes, occurring six days after ovulation and retained for 24 hours during the implantation window.
The pinopods express chemokines and CAMs, which attract the blastocyst floating within the endometrial cavity to appose. Additionally, the smooth surface of the pinopodes facilitates the apposition of the blastocyst to the endometrium. Further encouraging the blastocyst to appose to the pinopods is the removal of adhesion inhibiting mucin, while the areas between pinopods have been shown to express MUC-1, which prevents embryo adhesion 5.
Once the blastocyst is apposed, a stronger attachment is achieved through local paracrine aling between the embryo and the endometrium. At this stage, the blastocyst is sufficiently adherent to the endometrium as to resist dislocation of the blastocyst by flushing the uterine lumen. The first of the attachment reaction coincides with a localized increase in stromal vascular permeability which is manifested as stromal edema at the site of blastocyst attachment 6. Thus, vascular changes also appear to be an important factor in establishing endometrial receptivity.
Following adhesion, the embryo invades through the luminal epithelium into the stroma to establish a relationship with the maternal vasculature. In response to this invasion and the presence of progesterone stimulation, the endometrial stromal cells undergo a process termed decidualization by which they differentiate and become specialized decidual stromal cells.
Decidualization is essential for the survival and continued development of the pregnancy. In humans, decidual changes occur throughout the entire endometrium during the luteal phase even in the absence of an embryo, but become widespread in early gestation.
These decidual stromal cells are very metabolically active and support the implanting embryo by secreting a wide array of hormones and growth factors including prolactin, relaxin, insulin-like growth factors IGFs and insulin growth factor binding proteins IGFBPs. The endometrial stromal cells are the precursors of decidual stromal cells and appear to originate from both resident uterine mesenchymal stem cells as well as adult bone marrow-derived stem cells 78. Interestingly, bone marrow-derived progenitors have been shown to give rise to functional prolactin-producing decidual stromal cells in decidua of pregnant mice, and appear to play an important role in implantation and pregnancy maintenance 9.
The bone marrow is also the source of many leukocytes that infiltrate the endometrium during the secretory phase. This gain in leukocyte s is primarily due to the accumulation of uterine natural killer uNK cells. Studies in mice additionally show that the selected entry of uNK cells into early decidua optimizes angiogenesis and promotes decidual spiral artery vascular remodeling.
This influences the timing of uterine lumen closure and thereby the appropriate rate of early fetal development including initiation of trophoblast invasion Macrophages are the second most abundant leukocyte population in the luteal phase endometrium.
In addition to uterine NK cells and macrophages, the endometrium contains T cells with no apparent cyclic changes, and rare populations of dendritic cells in luteal phase endometrium, both of which become more abundant in the pregnant decidua. The composition and function of these immune cells at the implantation site and the maternal-fetal interface are highly specialized to foster embryo and placental development and to minimize the chance of immune rejection Progesterone is essential in mediating the changes that the endometrium undergoes in the luteal phase in preparation for embryo implantation The effects of progesterone on the uterus have been elucidated through elegant experiments in knockout mice as well as studies using progesterone receptor PR antagonists.
Mice with global PR knockout are infertile due to defects in ovulation and implantation Their endometrium displays hypertrophy and inflammation of the glandular epithelium associated with failure to undergo decidualization. Mice with a specific knockout in PR-B isoform, however, have normal ovarian function, implantation and reproductive capacity 15 In contrast, mice with a specific knockout in PR-A exhibit lack of decidualization in Man to pregnant woman tf endometrial stroma along with endometrial epithelial hyperplasia and inflammation 1516indicating that PR-A is critical for embryo implantation and the normal function of the endometrial epithelium and stroma, while PR-B promotes epithelial hyperplasia of the endometrium.
Moreover, administration of the progesterone antagonist mifepristone RU in humans during pregnancy induces abortion, fetal loss or parturition, depending on the gestational age 17 If administered at low doses at the mid- or late follicular phase, it prevents pregnancy by delaying endometrial maturation, while at high doses it delays the LH surge and inhibits ovulation 19 The key to endometrial receptivity is the dynamic and precisely controlled molecular and cellular events that involve coordinated effects of autocrine, paracrine, and endocrine factors.
In particular, transcription factors such as the homeobox HOX genes are essential for endometrial receptivity by mediating some functions of the sex steroids. Both HOXA10 and HOXA11 mRNAs are expressed in human endometrial epithelial and stromal cells; their expression is upregulated by estrogen and progesterone, and is ificantly higher in the mid- and late-secretory phases, coinciding with time of embryo implantation 24 Other growth factors, cytokines, and transcription factors produced by the endometrium also assist in the establishment of endometrial receptivity 26 Impaired endometrial receptivity is considered to be a major limiting factor for the establishment of a pregnancy.
Pregnancy-related proteins can be found in maternal circulation shortly after fertilization. For example, platelet activating factor PAF -like substance, which is produced by the fertilized ovum, is present almost Man to pregnant woman tf 29 - After ovulation and fertilization, the embryo remains in the ampullary portion of the fallopian tube for up to 3 days. The embryo undergoes a sequence of cell divisions and differentiation that is not dependent on the hormonal milieu of the fallopian tube or the uterus, as fertilization and early embryonic development occur successfully in vitro.
The developing conceptus travels toward the uterus, through the isthmic portion of the tube, for approximately 10 hours, and then enters the uterus as an embryo Man to pregnant woman tf the 2- to 8-cell stage 33 With further development, between days after fertilization, the embryo becomes a blastocyst floating unattached in the endometrial cavity A schematic representation of the pre-implantation phase of pregnancy is shown in Figure 2.
Before implantation, the blastocyst also secretes specific substances that enhance endometrial receptivity. Successful implantation requires precise synchronization between blastocyst development and endometrial maturation. Indeed, there appears to be a cross-talk between the embryo and the endometrium with the endometrium acting as a biosensor that is able to respond favorably to competent embryos but less favorably to incompetent poorly viable embryos destined to fail Ultimately, implantation failure is the result of impaired embryo developmental competence or impaired endometrial receptivity, both having negative effects on the embryo-endometrium cross-talk.
It is estimated that embryos for one third of implantation failures, while suboptimal endometrial receptivity and aberrant embryo-endometrial cross-talk are responsible for the remaining two-thirds A diagrammatic summary of the ovarian cycle leading to embryo development as it occurs during the first week after fertilization. Adapted Man to pregnant woman tf 37with permission. To date, little information exists regarding regulation of steroid production in the embryo. The early embryo and its surrounding cumulus cells secrete detectable estradiol and progesterone well before the time of implantation 38 Mechanical removal of these cells in the cessation of steroid secretion, while return of the removed cells through co-culture in restoration of steroid secretion Given this finding, steroid production by the conceptus is thought to be negligible by the time it has reached the endometrial cavity, since it is gradually denuded of cumulus cells as it travels through the fallopian tube.
Conceptus-secreted progesterone may itself affect tubal motility as the conceptus is carried to the uterus Progesterone, by action mediated through catecholamines and prostaglandins PGis believed to relax utero-tubal musculature. Moreover, progesterone is thought to be important in tubal-uterine transport of the embryo to the uterine cavity, since receptors for progesterone are found in highest concentrations in the mucosa of the distal one third of the fallopian tube.
Estradiol, also secreted by these structures, may balance the progesterone effect so as to maintain the desired level of tubal motility and tone Progesterone antagonizes estrogen-augmented uterine blood flow through depletion of estrogen receptors in the cytoplasm Likewise, estrogen and progesterone also appear to balance one another in the maintenance of blood flow at the implantation site.Man to pregnant woman tf
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