Saturday, 2 November 2013


                                                              Ovarian Cycle
At puberty, the female begins to undergo regular monthly cycles. Thesesexual cyclesare controlled
by the hypothalamus.Gonadotropin-releasing hor-mone (GnRH)produced by the hypothalamus acts on
cells of the anterior pituitary gland, which in turn secrete gonadotropins. These hormones, follicle-stimulating
hormone (FSH)andluteinizing hormone (LH), stimulate and control cyclic changes in the ovary.
At the beginning of each ovarian cycle, 15 to 20 primary (preantral) stage follicles are stimulated to grow under the influence of FSH. (The hormone is not necessary to promote
development of primordial follicles to the primary follicle stage, but without it, these primary follicles die and become atretic.) Thus,FSH rescues 15 to 20 of these cells from a pool of continuously
forming primary follicles. Under normal conditions, only one of these follicles reaches full maturity, and only one oocyte is discharged; the others degenerate and become atretic. In the next cycle, another group of primary follicles is recruited, and again, only one follicle reaches maturity. Consequently, most follicles degenerate without ever reaching full maturity. When a follicle becomes atretic, the oocyte and surrounding follicular cells degenerate and are replaced by connective tissue, forming acorpus atreticum.FSH also stimulates maturation offollicular (granulosa) cells surrounding the oocyte. In turn, proliferation of these cells is mediated by growth differentiation.factor-9 (GDF-9), amember of the transforming growth factor-β(TGF-β) family.
In cooperation, granulosa and thecal cells produce estrogens that (a) cause the uterine endometrium to enter the follicular orproliferative phase;(b) cause thinning of the cervical mucus to allow passage of sperm; and (c) stimulate the pituitary gland to secrete LH.
At mid-cycle, there is anLH surgethat (a) ele-vates concentrations of maturation-promoting factor, causing oocytes to com-pletemeiosis I and initiatemeiosis II; (b) stimulates production of progesterone by follicular stromal cells(luteinization);and (c) causes follicular rupture and ovulation.
In the days immediately preceding ovulation, under the influence of FSH and LH, the secondary follicle grows rapidly to a diameter of 25 mm. Coincident with final development of the secondary follicle, there is an abrupt increase in LH that causes the primary oocyte to completemeiosis I and the follicle to enter
the preovulatory stage. Meiosis II is also initiated, but the oocyte is arrested in metaphase approximately 3 hours before ovulation. In the meantime, the sur-face 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 con-tractions 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 thecorona radiata
                 CLINICAL CORRELATES

During ovulation, some women feel a slight pain, known asmiddle pain because it normally occurs near the middle of the menstrual cycle. Ovulation is also generally accompanied by a rise in basal temperature, which can be monitored to aid in determining when release of the oocyte occurs. Some women fail to ovulate because of a low concentration of gonadotropins. In these cases, administration of an agent to stimulate gonadotropin release and hence ovulation can be employed. Although such drugs are effective, they often produce multiple ovulations, so that the risk of multiple pregnancies is 10 times higher in these women than in the general population.

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 lutean cells,which form the corpus luteumand secrete the hormone progesterone. Progesterone, together with estrogenic hor-mones, causes the uterine mucosa to enter the progestationalor secretory stage in preparation for implantation of the embryo.

Shortly before ovulation, fimbriae of the oviduct begin to sweep over the surface of the ovary, and the tube itself begins to contract rhythmically. It is thought that the oocyte surrounded by some granulosa cells (Figs. 2.3 and 2.4) is carried into the tube by these sweeping movements of the fimbriae and by motion of cilia on the epithelial lining. Once in the tube, cumulus cells withdraw their cytoplasmic processes fromthe zona pellucida and lose contact with the oocyte. Once the oocyte is in the uterine tube, it is propelled by cilia with the rate of transport regulated by the endocrine status during and after ovulation. In humans, the fertilized oocyte reaches the uterine lumen in approximately 3 to 4 days.

If fertilization does not occur, the corpus luteum reaches maximum development approximately 9 days after ovulation. It can easily be recognized as a yellowish projection on the surface of the ovary. Subsequently, the corpus luteum shrinks because of degeneration of lutean cells and forms a mass of fibrotic scar tissue, thecorpus albicans.Simultaneously, progesterone production de-creases, precipitating menstrual bleeding. If the oocyte is fertilized, degener-ation of the corpus luteum is prevented by human chorionic gonadotropin (hCG), a hormone secreted by the syncytiotrophoblast of the developing em-bryo. The corpus luteum continues to grow and forms thecorpus luteum of pregnancy (corpus luteum graviditatis).By the end of the third month, this structure may be one-third to one-half of the total size of the ovary. Yellowish luteal cells continue to secrete progesterone until the end of the fourth month;thereafter, they regress slowly as secretion of progesterone by the trophoblastic component of the placenta becomes adequate for maintenance of pregnancy. Removal of the corpus luteum of pregnancy before the fourth month usually leads to abortion.

Fertilization, the process by which male and female gametes fuse, occurs in the ampullary region of the uterine tube.This is the widest part of the tube and Fertilization.Fertilization, the process by which male and female gametes fuse, occurs in the ampullary region of the uterine tube.This is the widest part of the tube and is close to the ovary Spermatozoa may remain viable in the female reproductive tract for several days.Only 1% of sperm deposited in the vagina enter the cervix, where theymay survive formany hours. Movement of sperm from the cervix to the oviduct is accomplished primarily by their own propulsion, although they may be assisted by movements of fluids created by uterine cilia. The trip from cervix to oviduct requires a minimum of 2 to 7 hours, and after reaching the isth-mus, 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. Spermatozoa are not able to fertilize the oocyte immediately upon arrival in the female genital tract but must undergo
(b)the acrosome reaction to acquire this capability.
Capacitationis a period of conditioning in the female reproductive tract that in the human lasts approximately 7 hours. Much of this conditioning,which occurs in the uterine tube, entails epithelial interactions between the sperm and mucosal surface of the tube. During this time a glycoprotein coat and seminal plasma proteins are removed from the plasma membrane that overlies the acrosomal region of the spermatozoa. Only capacitated sperm can pass through the corona cells and undergo the 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 sub-stances.The phases of fertilization include phase 1, penetration of the corona ra-diata; phase 2, penetration of the zona pellucida; and phase 3, fusion of the oocyte and sperm cell membranes.

Of the 200 to 300 million spermatozoa 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. Capacitated sperm pass freely through corona cells.

The zona is a glycoprotein shell surrounding the egg that facilitates and main-tains sperm binding and induces the acrosome reaction. Both binding and the acrosome reaction are mediated by the ligand ZP3, a zona protein. Release of acrosomal enzymes (acrosin) allows sperm to penetrate the zona, thereby coming in contact with the plasma membrane of the oocyte. Per-meability of the zona pellucida changes when the head of the sperm comes in contact with the oocyte surface. This contact results in release of lysosomal enzymes from cortical granules lining the plasma membrane of the oocyte.In turn, these enzymes alter properties of the zona pellucida (zona reaction) to prevent sperm penetration and inactivate species-specific receptor sites for spermatozoa on the zona surface. Other spermatozoa have been found embedded in the zona pellucida, but only one seems to be able to penetrate the oocyte.


The initial adhesion of sperm to the oocyte is mediated in part by the interaction of integrins on the oocyte and their ligands, disintegrins, on sperm. After adhesion, the plasmamembranes of the sperm and egg fuse. Because the plasma membrane covering the acrosomal head cap disappears during the acrosome reaction, actual fusion is accomplished between the oocyte membrane and the membrane that covers the posterior region of the sperm head. In the human, both the head and tail of the spermatozoon enter the cytoplasm of the oocyte, but the plasmamembrane is left behind on the oocyte surface. As soon as the spermatozoon has entered the oocyte, the egg responds in three ways:
1. Cortical and zona reactions.As a result of the release of cortical oocyte granules, which contain lysosomal enzymes, (a) the oocyte membrane becomes impenetrable to other spermatozoa, and (b) the zona pellu-cida alters its structure and composition to prevent sperm binding and penetration. These reactions prevent polyspermy (penetration of more than one spermatozoon into the oocyte).
2. Resumption of the second meiotic division.The oocytefinishes its sec-ond meiotic division immediately after entry of the spermatozoon. One of the daughter cells, which receives hardly any cytoplasm, is known as the second polar body the other daughter cell is the definitive oocyte.Its chromosomes (22+X) arrange themselves in a vesicular nucleus known as the female pronucleus.
3. Metabolic activation of the egg.The activating factor is probably car-ried by the spermatozoon. Post fusion activation may be considered to encompass 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(Fig. 2.6); the tail detaches and degenerates. Morphologically, the male and female pronuclei are indistinguishable, and eventually, they come into close contact and lose their nuclear envelopes. During growth of male and female pronuclei (both haploid), each pronucleus must replicate its DNA.If it does not, each cell of the two-cell zygote has only half of the normal amount of DNA. Immediately after DNA synthesis, chromosomes organize on the spindle in preparation for a normal mitotic division. The 23 maternal and 23 paternal (double) chromosomes split longitudinally at the centromere, and sister chromatids move to opposite poles, providing each cell of the zygote with the normal diploid number of chromosomes and DNA.As sister chromatids move to opposite poles, a deep furrow appears on the surface of the cell, gradually dividing the cytoplasm into two parts .
The main results of fertilization are as follows:
Restoration of the diploid number of chromosomes,half from the fa-ther and half from the mother. Hence, the zygote contains a new combination of chromosomes different from both parents 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. Hence, the chromosomal sex of the embryo is determined at  fertilization
Initiation of cleavage.
Without fertilization, the oocyte usually degenerates 24 hours after ovulation.
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. However, after the third cleavage, 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(mulberry).Inner cells of the morula constitute the inner cell mass,and surrounding cells compose theouter 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.

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 theembryoblast,are at one pole, and those of the outer cell mass, ortrophoblast, flatten and form the epithelial wall of the blastocyst. The zona pellucid has disappeared, allowing implantation to begin.
In the human, trophoblastic cells over the embryoblast pole begin to pen-etrate between the epithelial cells of the uterine mucosa about the sixth day.Attachment and invasion of the trophoblast involve integrins, ex-pressed by the trophoblast, and the extracellular matrix molecules laminin and fibronectin. Integrin receptors for laminin promote attachment, while 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. Hence, by the end of the first week of development, the human zygote has passed through the morula and blastocyst stages and has begun implantation in the uterine mucosa.
Uterus at Time of Implantation
The wall of the uterus consists of three layers: (a) endometriumor mu-cosa lining the inside wall; (b) myometrium,a thick layer of smooth muscle; and (c) perimetrium,the peritoneal covering lining the outside wall. From puberty (11–13 years) until menopause (45–50 years), the endometrium undergoes changes in a cycle of approximately 28 days under hormonal control by the ovary. During this menstrual cycle, the uterine en-dometrium passes through three stages, the follicularor proliferative phase, thesecretoryorprogestational phase,and themenstrual phase(Figs. 2.11–
2.13). The proliferative phase begins at the end of themenstrual phase, is under
the influence of estrogen, and parallels growth of the ovarian follicles. The se-cretory phase begins approximately 2 to 3 days after ovulation in response to progesterone produced by the corpus luteum. If fertilization does not occur,shedding of the endometrium (compact and spongy layers) marks the begin-ning of themenstrual phase. If fertilization does occur, the endometriu mass implantation and contributes to formation of the placenta.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,and a thinbasal layer(Fig. 2.12). Normally, the human blastocyst implants in the endometrium along the anterior or posterior wall of the body of the uterus, where it becomes embedded between the openings of the glands.If the oocyte is not fertilized, venules and sinusoidal spaces gradually become packed with blood cells, and an extensive diapedesis of blood into the tissue is seen. When the menstrual phase begins, blood escapes from superficial arteries, and small pieces of stroma and glands break away.During the following 3 or 4 days, the compact and spongy layers are expelled from the uterus, and the basal layer is the only part of the endometrium that is retained This layer, which is supplied by its own arteries, the  basal arteries,functions as the regenerative layer in the rebuilding of glands and arteries in the proliferative phase.