Pregnancy and Fertility

Most doctors consider the first day of the last menstrual period to be the beginning of pregnancy. This period is called "menstrual age," it begins about two weeks before fertilization. The following is the basic information about fertilization:

[1], [2], [3]

Ovulation

Each month, in one of the female ovaries, a certain number of unripe eggs begin to develop in a small bubble filled with liquid. One of the vials completes the maturation. This "dominant follicle" suppresses the growth of other follicles, which stop growing and degenerate. The mature follicle breaks and releases eggs from the ovary (ovulation). Ovulation occurs, as a rule, two weeks before the beginning of the nearest menstrual period in a woman.

Development of the yellow body

After ovulation, the ruptured follicle develops into an entity called the yellow body that secretes two kinds of hormones, progesterone and estrogen. Progesterone promotes the preparation of the endometrium (mucous membrane of the uterus) to embryo embedding, thickening it.

[4], [5], [6], [7]

Egg release

The egg is released and enters the fallopian tube, where it remains until at least one sperm enters it during fertilization (egg and sperm, see below). The egg can be fertilized within 24 hours after ovulation. On average, ovulation and fertilization occur two weeks after the last menstrual period.

[8], [9], [10], [11]

Menstrual cycle

If the sperm does not fertilize the egg, it and the yellow body degenerate; will disappear and an elevated level of hormones. Then there is a rejection of the functional layer of the endometrium, which leads to menstrual bleeding. The cycle repeats.

Fertilization

If a sperm enters a mature egg, it fertilizes it. When a sperm enters the egg, a change takes place in the protein shell of the egg cell, which no longer allows sperm to enter. At that moment genetic information about the child, including his gender, is laid. Mother gives only X-chromosomes (mother = XX); if the spermatozoon-U fertilizes the ovum, the child will be male (XY); if fertilizes the sperm-X, a girl (XX) will be born.

Fertilization is not just a summation of the nuclear material of the egg and sperm - it is a complex set of biological processes. The oocyte is surrounded by granule cells, which are called corona radiata. Between corona radiata and the oocyte, zona pellucida is formed, which contains specific receptors for spermatozoa, preventing polyspermy and providing movement of the fertilized egg through the tube to the uterus. Zona pellucida consists of glycoproteins secreted by the growing oocyte.

Meiosis resumes during ovulation. The resumption of meiosis is observed after the preovulatory peak of LH. Meiosis in a mature oocyte is associated with the loss of a nuclear membrane, the collection of chromatin by bivalent, the separation of chromosomes. Meiosis ends with the liberation of the polar body during fertilization. For a normal meiosis process, a high concentration of estradiol in the follicular fluid is necessary.

Male germ cells in the seminiferous tubules as a result of mitotic division form the first order spermatocytes, which pass through several stages of maturation, like a female ovum. As a result of meiotic division, spermatocytes of the second order are formed, containing half the number of chromosomes (23). Spermatocytes of the second order mature to spermatids and, no longer undergoing division, turn into spermatozoa. A set of successive stages of maturation is called a spermatogenic cycle. This cycle in a man is performed in 74 days and undifferentiated spermatogonia turns into a highly specialized sperm that can move independently, and has a set of enzymes necessary for penetration into the egg. Energy for movement is provided by a variety of factors including cAMP, Ca ²⁺, catecholamines, protein mobility factor, protein carboxymethylase. Spermatozoa present in fresh semen are incapable of fertilization. This ability they acquire, getting into the female genital tract, where they lose the envelope antigen - there is a capation. In turn, the egg releases a product that dissolves the acrosomal vesicles that cover the sperm head, where the genetic fund of paternal origin is located. It is believed that the process of fertilization takes place in the ampullar section of the tube. The tube funnel actively participates in this process, densely adjoining to a site of an ovary with an outstanding on its surface a follicle and, as though, sucks an ootid. Under the influence of enzymes isolated by the epithelium of the fallopian tubes, the egg cell is released from the cells of the radiant crown. The essence of the process of fertilization consists in the unification, the fusion of the female and male sex cells, separated from the organisms of the parent generation into one new cell - the zygote, which represents not only the cell but also the organism of the new generation.

Sperm introduces into the egg mainly its nuclear material, which combines with the nuclear material of the egg into a single nucleus of the zygote.

The process of maturation of the egg and the process of fertilization are provided by complex endocrine and immunological processes. Because of ethical problems, these processes in humans have not been studied enough. Our knowledge is mainly derived from animal experiments, which have a lot in common with these processes in humans. Thanks to the development of new reproductive technologies in in vitro fertilization programs, the stages of development of the human embryo to the blastocyst stage in vitro were studied. Thanks to these studies, a great deal of material was accumulated on the study of the mechanisms of early development of the embryo, its advancement through the tube, and implantation.

After fertilization, the zygote advances through the tube, undergoing a complex developmental process. The first division (the stage of two blastomeres) occurs only on the 2nd day after fertilization. As you move along the pipe in the zygote, a complete asynchronous crushing takes place, which leads to the formation of a morula. By this time, the embryo is released from the vitelline and transparent membranes and in the morula stage the embryo enters the uterus, representing a loose complex of blastomeres. Passage through the tube is one of the critical moments of pregnancy. It was established that the relationship between the homomet / early embryo and the epithelium of the fallopian tube is regulated autocrine and paracrine, providing an embryo with a medium that enhances the processes of fertilization and early development of the embryo. Believe it. That the regulator of these processes is gonadotropic releasing hormone, produced both by a preimplantation embryo and by the epithelium of the fallopian tubes.

The tubal epithelium expresses GnRH and GnRH receptors as ribonucleic acid (mRNA) messengers and proteins. It turned out that this expression is cyclic-dependent and, mainly, appears during the luteal phase of the cycle. Based on these data, a group of researchers believe that GnRH tubes play a significant role in autocrine-paracrine regulation in fertilization, early embryo development and vimplantation, since there are a significant number of GnRH receptors in the uterine epithelium during the maximum development of the "implantation window".

It has been shown that GnRH, mRNA and protein expression are observed in the embryo, and it increases as the morula turns into a blastocyst. It is believed that the interaction of the embryo with the epithelium of the tube and with the endometrium is carried out through the GnRH system, which ensures the development of the embryo and the receptivity of the endometrium. Again, many researchers emphasize the need for synchronous development of the embryo and all mechanisms of interaction. If embryo transport for some reason can be delayed, the trophoblast may exhibit its invasive properties before entering the uterus. In this case, tubal pregnancy may occur. With rapid progression, the embryo enters the uterus, where there is still no receptivity of the endometrium and implantation may not occur, or the embryo lingers in the lower parts of the uterus, i.e. In a place less suitable for further development of the fetal egg.

[12], [13],

Implantation of ovum

Within 24 hours after fertilization, the egg begins to actively divide into cells. It is in the fallopian tube for about three days. The zygote (the fertilized egg) continues to divide, slowly moving along the fallopian tube to the uterus, where it joins the endometrium (implantation). First, the zygote turns into a cluster of cells, then becomes a hollow ball of cells, or a blastocyst (an embryonic bladder). Before implantation, the blastocyst emerges from the protective coating. When the blastocyst approaches the endometrium, the exchange of hormones contributes to its attachment. Some women have spots or slight bleeding for several days during the implantation period. Endometrium becomes thicker and the cervix is isolated by mucus.

For three weeks blastocyst cells grow into a cluster of cells, the first nerve cells of the child are formed. A child is called an embryo from the moment of fertilization to the eighth week of pregnancy, after which, before birth, it is called the fetus.

The implantation process can only be if the embryo entering the uterus has reached the blastocyst stage. The blastocyst consists of the inner part of the cells - the endoderm, from which the embryo itself is formed, and the outer layer of cells - the trophoectoderm - the precursor of the placenta. It is believed that at the preimplantation stage, the blastocyst expresses preimplantation factor (PIF), vascular endothelial growth factor (VEGF), as well as mRNA and protein to VEGF, which allows the embryo to very quickly carry out angiogenesis for successful placentation and creates the necessary conditions for its further development .

For successful implantation, it is necessary that all the required changes in the differentiation of endometrial cells appear in the endometrium for the appearance of the "implantation window", which is normally observed on the 6-7th day after ovulation and that the blastocyst reaches a certain stage of maturity and proteases are activated that will promote the blastocyst in the endometrium. "Endometrial receptivity is the culmination of a complex of temporal and spatial changes in the endometrium, regulated by steroid hormones." The processes of the appearance of the "implantation window" and the maturation of the blastocyst should be synchronous. If this does not happen, the implantation will not take place or the pregnancy will be interrupted in its early stages.

Before implantation, the superficial epithelium of the endometrium is covered with mucin, which prevents premature blastocyst implantation and protects against infection, especially Mis1-episialin, which plays a barrier role in various aspects of the physiology of the female reproductive tract. By the time the "implantation window" is opened, the amount of mucin is destroyed by the proteases produced by the embryo.

Implantation of the blastocyst into the endometrium involves two stages: stage 1 - adhesion of two cellular structures, and 2 stage - decidualization of the endometrial stroma. An extremely interesting question, how an embryo identifies the place of implantation, is still open. From the moment the blastocyst enters the uterus, 2-3 days pass before the implantation begins. It is hypothetically assumed that the embryo secretes soluble factors / molecules, which, acting on the endometrium, prepare it for implantation. In the process of implantation, the key role belongs to adhesion, but this process, which allows to keep two different cellular masses, is extremely complicated. A lot of factors take part in it. It is believed that integrins play a leading role in adhesion at the time of implantation. Especially significant is integrin-01, its expression increases at the time of implantation. However, integrins themselves are devoid of enzymatic activity and should be associated with proteins to generate a cytoplasmic signal. Studies conducted by a team of researchers from Japan showed that small guanosine triphosphate-binding proteins RhoA convert integrins into active integrin, which is able to participate in cell adhesion.

In addition to integrins, adhesion molecules are such proteins as trifinin, butin and tastin (trophinin, bustin, tastin).

Trophinine is a membrane protein that is expressed on the surface of the endometrial epithelium at the site of implantation and on the apical surface of the trophectoid blastocyst. Bustin and tastin-cytoplasmic proteins in association with trophinine form an active adhesive complex. These molecules are involved not only in implantation, but also in the further development of the placenta. The molecules of the extracellular matrix, osteocanthine and laminin, are involved in adhesion.

An extremely large role is assigned to various growth factors. The researchers pay special attention to the importance of insulin-like growth factors and their binding proteins, especially IGFBP, in implantation. These proteins play a role not only in the implantation process, but also in modeling of vascular reactions, regulation of myometrium growth. According to Paria et al. (2001), a significant place in implantation processes is played by heparin-binding epidermal growth factor (HB-EGF), which is expressed both in the endometrium and in the embryo, as well as fibroblast growth factor (FGF), bone morphogenic protein (BMP), etc. After the adhesion of two cellular endometrial and trophoblast systems, the trophoblast invasion phase begins. Trophoblast cells secrete protease enzymes that allow the trophoblast to "squeeze" itself between cells into the stroma, lysing the extracellular matrix with the enzyme metalloprotease (MMP). Insulin-like growth factor of trophoblast II is the most important growth factor of trophoblast.

At the time of implantation, the entire endometrium is permeated with immunocompetent cells - one of the most important components of trophoblast interaction with the endometrium. The immunological relationship between the embryo and the mother during pregnancy is similar to the relationship that is observed in the transplant-recipient reactions. It was believed that implantation into the uterus is controlled in a similar way, through T cells that recognize the fetal alloantigens expressed by the placenta. However, recent studies have shown that implantation can involve a new way of allogeneic recognition based on NK cells faster than on T-cells. On the trophoblast, the antigens of the HLAI and class II system are not expressed, but the polymorphic antigen HLA-G is expressed. This antigen of paternal origin serves as an adhesion molecule for CD8 antigens of large granular white blood cells, the number of which increases in the endometrium in the middle of the lutein phase. These NK cells with CD3-CD8 + CD56 + markers are functionally more inert in production with Th1 bound by cytokines such as TNFcc, IFN-y compared to CD8-CD56 + decidual granular leukocytes. In addition, trophoblast expresses low binding ability (affinity) receptors for cytokines TNFa, IFN-y and GM-CSF. As a result, there will be predominantly a response to the fruit antigens caused by the response via Th2, i. E. Will predominantly produce non-pro-inflammatory cytokines, but, on the contrary, regulatory (il-4, il-10, il-13, etc.). The normal balance between Th 1 and Th 2 contributes to a more successful invasion of the trophoblast. Excessive production of pro-inflammatory cytokines limits the invasion of the trophoblast and delays the normal development of the placenta, in connection with which the production of hormones and proteins decreases. In addition, YOU cytokines increase prothrombinase activity and activate coagulation mechanisms, cause thrombosis and trophoblast detachment.

In addition, immunosuppressive conditions affect the molecules produced by the fetus and amnion - fetuin ( fetuin) and spermine ( spermine). These molecules suppress the production of TNF. Expression on trophoblast cells HU-G inhibits the NK-cell receptors thus also reduces immunological aggression against the intrusive trophoblast.

Decidual stromal cells and NK cells produce cytokines GM-CSF, CSF-1, aINF, TGFbeta, which are necessary for growth and development of trophoblast, proliferation and differentiation.

As a result of growth and development of the trophoblast, the production of hormones increases. Especially essential for immune relationships is progesterone. Progesterone stimulates locally the production of placental proteins, especially protein-TJ6, binds the decidual leukocytes CD56 + 16 +, causing their apoptosis (natural cell death).

In response to trophoblast growth and invasion of the uterus to spiral arterioles, the mother produces antibodies (blocking) that have an immunotrophic function and block the local immune response. The placenta becomes an immunologically privileged organ. With a normally developing pregnancy, this immune balance is established by 10-12 weeks of pregnancy.

Pregnancy and hormones

Human chorionic gonadotropin is a hormone that occurs in the mother's blood from the moment of fertilization. It is produced by the cells of the placenta. It is a hormone that is fixed by a pregnancy test, however, its level becomes high enough to be determined only 3-4 weeks after the first day of the last menstrual cycle.

Stages of development of pregnancy are called trimester, or 3-month periods, because of the significant changes that occur at each stage.