First Week of Development: Ovulation to Implantation

First Week of Development: Ovulation to Implantation OVARIAN CYCLE At puberty, the female begins to undergo regular monthly cycles. Ovulation: At the beginning of each ovarian cycle, 15 to 20 primary-stage (preantral) follicles are stimulated to grow under the influence of FSH. Under normal conditions, only one of these follicles reaches full maturity, and only one oocyte is discharged; the others degenerate and become atretic. FSH also stimulates maturation of follicular (granulosa) cells surrounding the oocyte. In turn, proliferation of these cells is mediated by growth differentiation factor 9, a member of the transforming growth factor- β(TGF-β)family. In cooperation, theca interna and granulosa cells produce estrogens: Theca interna cells produce androstenedione and testosterone,and granular cells convert these hormones to estrone and 17 β -estradiol. As a result of this estrogen production: ■ The uterine endometrium enters the follicular or proliferative phase. ■ Thinning of the cervical mucus occurs to allow passage of sperm. ■ The anterior lobe of the pituitary gland is stimulated to secrete LH. At midcycle, there is an LH surge that: ■ Elevates concentrations of maturation-promoting factor, causing oocytes to complete meiosis I and initiate meiosis II. ■ Stimulates production of progesterone by follicular stromal cells (luteinization) ■Causes follicular rupture and ovulation Ovulation A mature vesicular (graafian)Follicle: diameter of 25 mm Coincident with final development of the vesicular follicle, there is an abrupt increase in LH: Meiosis II is also initiated, but the oocyte is arrested in metaphase approximately 3 hours before ovulation. In the mean time, the surface of the ovary begins to bulge locally, and at the apex, an avascular spot, the stigma , appears. The high concentration of LH increases collagenase activity, resulting in digestion of collagen fibers surrounding the follicle. Prostaglandin levels also increase in response to the LH surge and cause local muscular contractions in the ovarian wall. Those contractions extrude the oocyte, which together with its Surrounding granulosa cells from the region of the cumulus oophorus breaks free (ovulation) and floats out of the ovary Some of the cumulus oophorus cells then Rearrange themselves around the zona pellucida to form the corona radiata. Corpus Luteum After ovulation, granulosa cells remaining in the wall of the ruptured follicle, together with cells from the theca interna, are vascularized by surrounding vessels. Under the influence of LH, these cells develop a yellowish pigment and change into lutein cells , which form the corpus luteum and secrete estrogens and progesterone Corpus Albicans If fertilization does not occur, the corpus luteum reaches maximum development approximately 9 days after ovulation. Subsequently, the corpus luteum shrinks because of degeneration of lutein cells (luteolysis) and forms a mass of fibrotic scar tissue, the corpus albicans If the oocyte is fertilized, degeneration of the corpus luteum is prevented by human chorionic gonadotropin , a hormone secreted by the syncytiotrophoblast of the developing embryo. The corpus luteum continues to grow and forms the corpus luteum of pregnancy (corpus luteum graviditatis). Yellowish luteal cells continue to secrete progesterone until the end of the fourth month. Oocyte Transport Shortly before ovulation, fimbriae of the uterine tube sweep over the surface of the ovary, and the tube itself begins to contract rhythmically. - sweeping movements of the fimbriae - motion of cilia on the epithelial lining. Once in the tube, cumulus cells withdraw their cytoplasmic processes from the zona pellucida and lose contact with the oocyte. Only 1% of sperm deposited in the vagina enter the cervix, where they may survive for many hours. The trip from cervix to oviduct can occur as rapidly as 30 minutes or as slow as 6 days. After reaching the isthmus, sperm become less motile and cease their migration. At ovulation, sperm again become motile, perhaps because of chemoattractants produced by cumulus cells surrounding the egg, and swim to the ampulla, where fertilization usually occurs. FERTILIZATION Fertilization, the process by which male and female gametes fuse, occurs in the ampullary region of the uterine tube. Spermatozoa are not able to fertilize the oocyte immediately upon arrival in the female genital tract but must undergo (1) capacitation (2) acrosome reaction to acquire this capability. Capacitation Much of this conditioning during capacitation occurs in the uterine tube and involves epithelial interactions between the sperm and the mucosal surface of the tube. These secretions cause a molecular change in the sperm plasma lemma (removal of de capacitating factor - semen proteins, results in increased membrane fluidity,). Takes 7 hr in humans During this time, a glycoprotein coat and seminal plasma proteins are removed from the plasma membrane that overlies the acrosomal region of the spermatozoa. Acrosome Reaction The acrosome reaction , which occurs after binding to the zona pellucida, is induced by zona proteins. This reaction culminates in the release of enzymes needed to penetrate the zona pellucida, including acrosin- and trypsin-like substances The plasma membrane covering the acrosomal head cap disappears during the acrosome reaction. The phases of fertilization : Phase 1: Penetration of the Corona Radiata Of the 200 to 300 million spermatozoa normally deposited in the female genital tract, only 300 to 500 reach the site of fertilization. Only one of these fertilizes the egg. It is thought that the others aid the fertilizing sperm in penetrating the barriers protecting the female gamete. Phase 2: Penetration of the Zona Pellucida The zona is a glycoprotein shell surrounding the egg that facilitates and maintains sperm binding and induces the acrosome reaction. Both binding and the acrosome reaction are mediated by the ligand ZP3, a zona protein. Phase 3: Fusion of the Oocyte and Sperm Cell Membranes The initial adhesion of sperm to the oocyte is mediated inpart by the interaction of integrins on the oocyte and their ligands, disintegrins, on sperm. After adhesion, the plasma membranes of the sperm and egg fuse. Actual fusion is accomplished between the oocyte membrane and the membrane that covers the posterior region of the sperm head As soon as the spermatozoon has entered the oocyte, the egg responds in three ways: 1. Cortical and zona reactions. 2. Resumption of the second meiotic division. 3. Metabolic activation of the egg. Oocyte Activation: The activating factor is probably carried by the spermatozoon. Activation encompasses the initial cellular and molecular events associated with early embryogenesis. The spermatozoon, meanwhile, moves forward until it lies close to the female pronucleus. Its nucleus becomes swollen and forms the male pronucleus The main results of fertilization are as follows: 1- Restoration of the diploid number of chromosomes 2- Determination of the sex of the new individual. An X-carrying sperm produces a female (XX) embryo, and a Y-carrying sperm produces a male (XY) embryo. 3- Initiation of cleavage. Without fertilization, the oocyte usually degenerates 24 hours after ovulation. CLEAVAGE Once the zygote has reached the two-cell stage, it undergoes a series of mitotic divisions, increasing the numbers of cells. These cells, which become smaller with each cleavage division, are known as blastomeres Until the eight-cell stage, they form a loosely arranged clump After the third cleavage, however, blastomeres maximize their contact with each other, forming a compact ball of cells held together by tight junctions. This process, compaction, segregates inner cells, which communicate extensively by gap junctions, from outer cells. Approximately 3 days after fertilization, cells of the compacted embryo divide again to form a 16-cell morula Inner cells of the morula constitute the inner cell mass , and surrounding cells compose the outer cell mass . The inner cell mass gives rise to tissues of the embryo proper , and the outer cell mass forms the trophoblast , which later contributes to the placenta . BLASTOCYST FORMATION About the time the morula enters the uterine cavity, fluid begins to penetrate through the zona pellucida into the intercellular spaces of the inner cell mass. Gradually, the intercellular spaces become confluent, and finally, a single cavity, the blastocele , forms . At this time, the embryo is a blastocyst . Cells of the inner cell mass, now called the embryoblast , are at one pole, and those of the outer cell mass, or trophoblast , flatten and form the epithelial wall of the blastocyst The zona pellucida has disappeared, allowing implantation to begin. In the human, trophoblastic cells over the embryoblast pole begin to penetrate between the epithelial cells of the uterine mucosa on about the sixth day New studies suggest that L-selectin on trophoblast cells and its carbohydrate receptors on the uterine epithelium mediate initial attachment of the blastocyst to the uterus. Selectins are carbohydrate-binding proteins involved in interactions between leukocytes and endothelial cells that allow leukocyte “capture” from flowing blood. A similar mechanism is now proposed for “capture” of the blastocyst from the uterine cavity by the uterine epithelium. Following capture by selectins, further attachment and invasion by the trophoblast involve integrins, expressed by the trophoblast and the extracellular matrix molecules laminin and fibronectin. Integrin receptors for laminin promote attachment, whereas those for fibronectin stimulate migration. These molecules also interact along signal transduction pathways to regulate trophoblast differentiation, so that implantation is the result of mutual trophoblastic and endometrial action. Uterus The wall of the uterus consists of three layers: 1. Endometrium or mucosa lining the inside wall 2. Myometrium , a thick layer of smooth muscle 3. Perimetrium , the peritoneal covering lining the outside wall From puberty (11 to 13 years) until menopause (45 to 50 years), the endometrium undergoes changes in a cycle of approximately 28 days under hormonal control by the ovaries. During this menstrual cycle, the uterine endometrium passes through three stages: 1. Follicular or proliferative phase 2. Secretory or progestational phase 3. Menstrual phase Uterus at time of implantation At the time of implantation, the mucosa of the uterus is in the secretory phase, during which time uterine glands and arteries become coiled and the tissue becomes succulent. As a result, three distinct layers can be recognized in the endometrium: - a superficial compact layer , - an intermediate spongy layer , - a thin basal layer