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Submitted by Dr. Hesham Al-Inany, M.D. Lecturer, Gynaecology & Obstetrics dept. Kasr El-Aini hospital, Cairo University, Egypt.

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The nature of the sperm-egg interaction during fertilization leads to the sharing of membrane components.


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Embryology of female genital system
Gamete micromanipulation techniques


The sperm and eggs arise from primordial germ cells (PGCs). These cells appear shortly after implantation when the embryo is composed of only a few thousand cells. Thus, PGC determination is one of the earliest events in embryogenesis. These cells arise very early in humans at about 4 weeks of gestation in the yolk sac endoderm and are easily recognized because they contain large amounts of the enzyme alkaline phosphatase.

The PGCs migrate by ameboid movement into the dorsal mesentery of the embryo and then laterally into the genital ridges that are near the site of the future kidneys. During migration, the PGCs divide to yield several thousands cells. At the time of their arrival in the genital ridge, the female and male embryos are morphologically indistinguishable. However, shortly after the PGCs take up residence in the genital ridge, at about 6 weeks of gestation in humans, a difference in the sexes becomes apparent: in females the genital ridge remains unchanged in morphology, whereas the male gonad develops sex cords.

In males, the PGCs become diploid spermatogonia . These cells divide by mitosis until puberty whereupon some of the spermatogonia become committed to meiosis. However, diploid spermatogonia persist throughout life and serve as a continous stem cell population.
The spermatogonia committed to meiosis become primary spermatocytes, and it is in these cells that genetic crossing over occurs. After completion of meiosis, the diploid spermatids develop a tail and a condensed head. During this process of spermiogenesis, the spermatids move toward the lumen of the testicular seminiferous tubule and are released into the lumen.

In females, the pattern of differentiation is markedly different. Shortly after arrival in the genital ridge, the female PGCs cease dividing and become primary oocytes. These cells replicate their DNA for the first meiotic division and then undergo crossing over. While still in the prophase of the first meiotic division and with the points of chromosome synapsis still visible, these cells then become arrested.

While eggs may remain in this state until puberty when menarche occurs, the majority resume meiosis I at varying times (in utero, infancy, prepuberty) only to be lost short of ovulation in atresia and resolution.

After menarche, in each menstrual cycle a few follicles will develop and proceed toward ovulation. During follicular growth, eggs move to metaphase of the first meiotic division. At ovulation, the first meiotic division is completed, the first polar body is released, and the eggs proceed to metaphase of the second meiotic division. Here they remain until fertilized, and it is only after fertilization that the egg completes meiosis and releases a second polar body.


The pattern of gene regulation during gametogenesis is among the most unusual of all cell types. In the male, a remarkable regulatory event occurs in the primary spermatocyte. In this diploid XY cell, the only functional X chromosome undergoes inactivation in a manner indistinguishable from lyonization of the supernumerary X in XX female somatic cells.

Thus, the primary spermatocyte is the only diploid cell in the mammals without an active X chromosome. When an additional X chromosome is present as in klinefelter's syndrome (XXY), only one of the two X chromosomes is inactivated, and meiosis does not occur. This accounts for sterility in Klinefilter's males.

The developing spermatozoon compensate for the total absence of genetic activity from its X chromosome probably through messenger RNA (mRNA) storage. The X-linked genes are transcribed, but their mRMA is stored for use after X inactivation. Another compensatory mechanism has been the evolution of autosomal genes encoding enzymes similar to those encoded by X-linked genes.

After meiosis in males, the entire haploid genome must be packaged into the sperm head for transport to the egg. Thus, during spermatogenesis very little gene transcription occurs, and the DNA becomes complexed with proteins that bind very tightly. A few genes do function even after meiosis, and the isolation and characterization of this highly specialized subset of genes are very active areas of research.

Sperm Maturation

After leaving the testis, a sperm is an elongated flagellated cell with numerous well developed mitochondria that supply energy for movement and with a condensed nucleus covered by the acrosome, a large structure containing a variety of enzymes.

However, at this stage sperm are not still motile and cannot fertilize eggs. They first pass through the epididymis where further modifications of the head and tail take place and where proteins synthesized by epididymal cells are applied to the sperm surface. Maturation events in the epididymis are androgen dependent.

By the time the sperm reach the distal cauda epididymis, they are prepared for entry into the female reproductive tract where they undergo further modifications prior to fertilization.
After ejaculation, the sperm is still not capable of fertilization. They first must undergo capacitation, a poorly understood process that leads to a characteristic activated pattern of motility. Capacitation involves removal of proteins that coat the sperm. Capacitation time varies among species but in general occurs within a few hours of ejaculation.

After capacitation, the sperm undergoes the acrosome reaction (AR). The acrosomal reaction leads to the release of the hydrolytic enzymes in the acrosome into the environment and exposure of the inner acrosomal membrane of the sperm.

The AR serves two main purposes:

  1. Release of enzymes as hyaluronidase and protease which aid dissolution of investments surrounding the oocyte. After ovulation the oocyte is surrounded with the cumulus oophorus, a cloud of cumulus cells held together with hyaluronic acid. Inside the cumulus is the zona pellucida (ZP), a glycoprotein shell around the egg. This structure must be traversed for fetilization to occur.
    The acrosomal protease acrosin can dissolve the ZP, and some of this enzyme remains associated with the inner acrosomal membrane after the AR. Presumably, this remaining enzyme is brought into contact with the ZP at the time of sperm binding. Then, through the force of sperm motility and digestion by acrosin, the sperm penetrates the zona and gains access to the oocyte surface.

  2. Expose proteins on the inner acrosomal membrane which mediates sperm binding to the oocyte surface. The egg surface has receptors specific for sperm proteins.
    In many species, initial binding to the zona occurs prior to the AR. The zona pellucida protein (ZP3) then induces the AR and the sperm penetrates to reach the perivitelline space. Thus, sperm which undergo the AR spontaneously prior to contact with zona cannot bind to it or penetrate.
    The precise sequence of events leading to sperm-egg fusion varies among species and is not entirely known for humans. In some species, sperm apparently bind to the ZP before undergoing the AR, while in others the AR is completed prior to zona binding.
    One consistent features of the fusion process is the probable role of sperm motility. Sperm do not swim to the site of fertilization but rather are brought there by fluid convection in the female tract. In all mammals, motility probably serves to aid the sperm in passing through the cumulus and zona.


As in spermatogenesis, gene regulation in oogenesis is highly unusual. Whereas the spermatocyte is the only diploid cell without an active X, the premeiotic oocyte is the only diploid cell in which more than one X chromosome is active.
At this stage of oogenesis, the inactive X chromosome is reactivated. Why the second X chromosome is reactivated is not clear, but failure to do so is severely deleterious to oogenesis. In humans with Turner's syndrome (XO), there exists only one X chromosome, and these individual are sterile.

Oocyte maturation

Fetal oocytes are arrested in the first prophase of meiosis shortly after chromsome crossing over. At this time, the nuclear membrane is still visible and is called germinal vesicle.
Some oocytes remain at this "dictyate" stage until the beginning of the menstrual cycle. With each cycle, a cohort of these follicles begins to develop and resume meiosis. One dominant follicle complete maturation and release an egg. At ovulation, the oocyte completes the first meiotic division and extrudes the first polar body and proceeds to metaphase of the second meiotic division, where it again arrests pending arrival of the sperm only after activation by the process of sperm-egg fusion meiosis is completed with extrusion of the second polar body and formation of a female pronucleus.


The nature of the sperm-egg interaction that constitutes the fertilization process is poorly understood but leads to the sharing of membrane components of the sperm and egg. At this time, the egg becomes "activated". The activation process leads to completion of meiosis, extrusion of the second polar body and the development of a block to polyspermia; preventing supernumerary sperm from entering the egg.

The block to polyspermia involves release of cortical granules - vesicles which underlie the plasma membrane prior to activation. Release of the cortical granule contents into the perivetilline space results in an alternation of the character of the ZP such that further sperm binding is blocked (Gordon, 1988).

The species specificity of the fertilization process is provided by the ZP and the oocyte membrane. It is rare for sperm of heterologous species to pass through the zona. However, once the ZP is removed, some oocytes such as those of the hamster, are penetrable by sperm from several other mammals, including man (Yanagimachi, 1981).
After sperm entry, both the oocyte and sperm haploid genomes decondense and appear as membrane-bound pronuclei-spheric bodies in the ooplasm. Sperm-specific proteins are removed from the DNA , and replication of the female and male genomes begins.
Over the next several hours the pronuclei swell and move toward the center of the cell. As the time for the first cleavage division approaches, the pronuclear membranes break down, and the chromosomes line up on the first mitotic spindle (Yanagimachi, 1981).
In human, the first cleavage division usually occurs within 40 hours. The four cell stage is reached by 50 hours, and the eight-cell stage occurs by 70 hours after fertilization The morula stage (60-150 cells) develops 3 days postfertilization.

Cleavage     Cleavage is the process of early mitotic cell divisons, which progressively reduce cell size. During cleavage, the total embryonic mass remains relatively constant. When the embryo has about 16 cells, its individual cells begin to adhere to one     another, and it coalesces into a morula (Latin for mulberry) shape.

Blastocyst Formation: A cavity forms in the morula when it enters the uterus.This cavitation is an important transition from homogeneous cells to differentiated cell function. This new structure is called a blastocyst. The blastocyst consists of an outer layer, the trophoblast, and an inner cluster of cells, the inner cell mass. Continued expansion of the blastocyst cavity eventually ruptures the protective zona pellucida (shell) surrounding the morula.   Before the morula makes contact with the uterine wall, the zona pellucida will be shed.

Implantation is the process in which the blastocyst attaches to and penetrates into the uterine wall. Upon contact with the uterine lining (the endometrium), newly defined trophoblast cells begin an invasive activity that gives the embryo access to the deeper layers of the uterine wall. The implanting trophoblast cells differentiate into two new cell types syncytiotrophoblasts and cytotrophoblasts. Syncytiotrophoblast cells grow without cell division throughout implantation, becoming large, multinucleate cells, or syncytia (meaning fused cells) Cytotrophoblasts, remain individually distinct, mononucleated cells that invade deeper into the uterine wall than the syncytiotrophoblasts.

(Quoted from Kase, principles and practice of clinical Gynecology, 1990)

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