The first week of embryonic development is filled with an eclectic arrangement of physical and biochemical changes. Each step is a part of a cascade of events that must be intricately coordinated in order to produce a healthy baby at the end of the thirty eight to forty week period. However, the events of the first week of gestation are highly dependent on prior events that create the ideal environment for fertilization and implantation to occur. This article aims at briefly reviewing the processes preceding fertilization. There will be detailed evaluation of the ovulation cycle, copulation, fertilization and the first week of development.
Formation of Gametes
Meiosis
Meiosis is a modified form of cellular division that results in the production of genetically unique haploid (containing 23 chromosomes) progeny from a mature diploid cell (contains 46 chromosomes). There are several differences between the typical form of cellular replication known as mitosis and the mechanism by which gametes (sex cells) are formed. The overall nomenclature of the stages of meiosis is similar to that of mitosis.
The differences are such that
- meiosis is divided into two stages – meiosis I and II
- prophase I has five subdivisions – leptotene, zygotene, pachytene, diplotene, and diakinesis
- prophase I also contains a stage during which there is exchange of genetic information between homologous pairs of chromosomes
- meiosis II does not have an interphase as there is very little time between the completion of meiosis I and the commencement of meiosis II
Spermatogenesis
There are staunch differences between spermatogenesis (the development of male gametes) and oogenesis (development of female gametes). Spermatogenesis commences at the onset of puberty with the aid of hormones from the hypothalamic – pituitary – gonadal axis. The chief hormone that stimulates spermatogenesis is testosterone. It is produced by Leydig cells within the testes and acts on the sertoli cells within the seminiferous tubules (also in the testes).
They eventually promote the transformation of spermatogonia to primary spermatocytes, which then form secondary spermatocytes and finally spermatids. Four haploid spermatids are the derived from each spermatogonium. The spermatids are round and must undergo further maturation to become spermatozoa in order to be effective in reproduction. Therefore, the cells enter the spermiogenesis phase; where the cells elongate, develop an acrosome and grown a tail. The finished, mature spermatocyte (i.e. spermatozoa) is subsequently stored within the epididymis until they are needed.
Oogenesis
Oogenesis on the other hand begins during intrauterine life. Oogonia begin to enlarge and proliferate as they become primary oocytes. They also enter the reduction replication process but are arrested in early prophase I. The primary oocytes are also enclosed within a thin layer of flat cells known as granulosa (follicular) cells. These cells are responsible for stalling the meiotic process until the onset of puberty. The primary oocyte and granulosa layer are collectively referred to as the primordial follicle.
At birth, there are roughly 2 million primordial follicles within the ovaries of the female infant. About 98% of these follicles will be reabsorbed during childhood; and of the remaining 2%, only about 400 primordial follicles will mature over the reproductive lifespan of the individual (i.e. from menarche to menopause). Also note that the use of chemical contraceptive methods (pills, patches, injections) significantly reduces the amount of follicles that mature.
Both the surrounding follicular cells and enclosed oocyte continue to develop. The follicular cells transition from squamous to cuboidal then columnar cells; following which they become stratified around the growing oocyte forming primary follicle . The surrounding cells are subsequently joined by the bi-layered theca folliculi. The hypothalamic – pituitary – gonadal axis also influences the maturation of the follicle and oocyte.
The primary oocyte only completes meiosis I after ovulation has occurred (i.e. the oocyte has been extruded from the follicle. The progeny of this division is a small, redundant first polar body and a significantly larger secondary oocyte. However, it is arrested in metaphase II until fertilization takes place. Prior to this evolution, the follicle develops a fluid filled antrum and becomes a secondary follicle.
The menstrual cycle
The hypothalamic – pituitary – gonadal axis not only promotes oocyte maturation, but it also acts on the endometrial lining of the uterus in order to prepare it for possible implantation. This is a cyclical process that occurs each month and is characterised by proliferation and shedding of the endometrial lining. The overall process is called the menstrual or endometrial cycle.
Menstrual phase
Day one of the cycle is marked by shedding of the inner lining of the uterus and usually lasts for about 5 to 7 days. This occurs as a result of a reduction in progesterone in cases where fertilization does not occur. Leading up to this point in time, the corpus luteum (structure that remains after a tertiary [Graafian] follicle ruptures), which is responsible for secreting progesterone, degenerates. Consequently, friable vessels and eroded endometrial lining bleeds and dead endometrium slough off. This is referred to as the menstrual phase.
Proliferative phase
Subsequently there is growth of the selected ovarian follicle and proliferation of the endometrial lining. This portion – also called the proliferative phase – usually lasts around 9 days and corresponds to an increase in estrogen secretion. Estrogen promotes repair of the superficial endometrium as well as an increase in the size and number of glands in the lining. It also acts on the spiral arteries that perfuse the endometrium, resulting in lengthening of these vessels.
Luteal phase
At the end of the proliferative phase, the Graafian follicle ruptures under the influence of luteinizing hormone, releasing the secondary oocyte. Recall that oocytes are immobile and consequently rely on the fimbriae of the fallopian tubes to sweep it into the ampulla. Several things occur during this period:
- The walls of the Graafian follicle involute and form the corpus luteum.
- Increased progesterone secreted from the corpus luteum results in engorgement of the epithelial glands of the endometrial lining.
- The secondary oocyte enters the ampulla of the fallopian tube, where it awaits fertilization. Whether or not fertilization occurs, the oocyte moves toward the uterine cavity via peristaltic forces of the tube.
This stage is called the luteal phase and it usually lasts about 13 days. Failure of fertilization to occur ushers in the ischemic phase. The unfertilized oocyte continues via peristaltic activity towards the uterine cavity where it degenerates and is reabsorbed. There is contraction of the spiral arteries and reduction in glandular secretions as the supply of supporting hormones decline. Extended period of spiral artery constriction results in venous stasis and ischemic necrosis of the endometrium.
Copulation
Arousal
Copulation or the act of sexual intercourse facilitates the deposition of seminal fluid from the penis into the vaginal vault. The process is quite multifaceted, involving psychosocial, biochemical and physiological components. Strictly from a biological perspective, arousal of males requires parasympathetic involvement in order to attain an erection. This results in vasodilation and filling of the bulbous cavernous with blood. Arousal in females also results in clitoral engorgement, but more importantly the glands of the vaginal vault secrete lubricants that facilitate penetrance.
Ejaculation
Following insertion of the penis into the vaginal orifice, a series of pelvic thrusting culminates in male (and possibly female) ejaculation. Ejaculation occurs in two phases. In the emission phase the semen migrates to the prostatic urethra via the ejaculatory ducts. In the ejaculatory phase, the vesical sphincter closes at the neck of the bladder (to prevent diversion of semen into the bladder), the bulbospongiosus and urethral muscles contract, resulting in expulsion of semen from the external urethral os.
The peristaltic contractions of the ductus deferens are regulated by the sympathetic nervous system. To aid in remembering this, recall that parasympathetic system allows the male to point (erection) and the sympathetic system allows the male to shoot (ejaculate). Roughly 400 million spermatocytes are expressed in the fornix of the vaginal and around the external os of the uterus.
Sperm motility
Motility of the sperm is affected by the environmental pH. Therefore the cells move slower in the acidic vagina, but increase in speed in the more alkali uterus. When the woman is ovulating, her cervical plug is less viscous, which makes it easier for spermatocytes to propel through the cervical os with their powerful tails. The enzyme vesiculase (product of the seminal glands) which was added to semen induces coagulation of some of the ejaculate. This process leads to the formation of a vaginal plug that can also reduce the possibility of backflow from the uterus to the vagina.
As the semen enters the uterus, prostaglandins that were added to the seminal fluid stimulate uterine contractions. This helps the spermatocytes to reach the fallopian tubes a lot faster, where they can meet a waiting secondary oocyte. Only about 200 sperm actually makes it to the ampulla of the fallopian tube.
Fertilization of the oocyte
The sperm that make it into the uterus undergo further processing in order to successfully fertilize an oocyte. Glands of the uterus and fallopian tubes release activating factors that remove the seminal protein and glycoprotein coating of the spermatocyte. These structures usually coat the outer surface of the acrosome and would otherwise prevent the acrosome reaction from occurring. The resultant spermatocytes are more active than they previously were; but they are still structurally identical to their previous state. Oocytes secrete chemotactic agents that attract the spermatocytes to their location.
The entire process takes about 24 hours to complete. It begins with the release of hyaluronic acid from the acrosome and production of tubal mucosal enzymes. The enzymes scatter the corona radiata (follicular cells) that surrounds the secondary oocyte, thus allowing the sperm to propel forward.
The spermatocyte then encounters the zona pellucida deep to the corona radiata. The acrosome will attach to zona pellucida sperm binding protein 3 (ZP3). This surface glycoprotein on the zona pellucida of the secondary oocyte, along with calcium ions, sperm plasma membrane, progesterone and prostaglandins are intricately involved in the impending acrosome reaction. The resulting channel that is formed releases acrosin, esterases and neuraminidase enzymes that lyse the zona pellucida. The spermatocyte can then follow the progressing pathway. Acrosin also stimulates the zona reaction, which renders the zona pellucida impermeable to successive spermatocytes.
Fusion of the spermatocyte and oocyte plasma membrane results in degradation of both plasma membranes at the point of contact. At this point, the secondary oocyte completes meiosis II and forms a mature oocyte. The second polar body that is generated from this division is extruded (along with the first).
The chromosomes of the mature oocyte then decondense and form a pronucleus. The nucleus of the spermatocyte also begins to enlarge within the cytoplasm of the mature oocyte and also forms a pronucleus. The resulting oocyte now has two haploid pronuclei within its membrane. At this stage it is referred to as an ootid. As the pronuclei fuse and the chromosomes mix, a single celled diploid zygote with a unique arrangement of chromosomes is formed. Chromosomal gender is dependent on the genotype of the fertilizing spermatocyte and is determined at the point of fertilization. If the spermatocyte was 23, Y then the genetic sex is male; while a 23, X spermatocyte would yield a genetic female.
Cleavage and migration of the zygote
The resulting zygote undergoes a series of mitotic division, which commences about 30 hours after fertilization has occurred. With each division, the progeny (known as blastomeres) become smaller. The blastomeres are retained within the zona pellucida. Peristaltic activity continues to move the dividing ball of cells from the fallopian tube into the uterine cavity. When there are more than 8 blastomeres within the zona pellucida, the cells undergo compaction, where each cell realigns with adjacent cells to maximize the space available. It also prepares the cells to separate into the inner and outer cell masses. Division continues and on the 3rd day after fertilization, there are 12 to 32 blastomeres clustered together. The resulting ball of cells is referred to as a morula.
The morula now arrives in the uterine cavity on the 4th day post fertilization. It begins to accumulate fluid from the uterine cavity via the fenestrated zona pellucida. The resulting fluid filled space separates the blastomeres into a thin outer trophoblast and a cluster of blastomeres. The trophoblast provides nourishment for the developing blastocyst and the inner cells – which will subsequently be referred to as the embryoblast – gives rise to the embryo. This overall stage is known as blastogenesis; and the product of conception is referred to as the blastocyst.
Early implantation of the blastocyst
As the blastocyst floats in the uterine cavity, there is degradation of the zona pellucida to facilitate rapid growth and expansion of the blastocyst. The embryo absorbs nutrients from the uterine secretions. On day 6 the trophoblasts differentiates into the cytotrophoblast and syncytiotrophoblast as the blastocyst attaches to the endometrium at the embryonic pole.
The syncytiotrophoblast (which is the outer layer of the blastocyst) extends papillary projections into the endometrium and releases enzymes that breaks down the maternal tissue. This allows further implantation of the blastocyst into the endometrium. Additionally, the embryo can derive more nutrients from the maternal cells as it continues to dig deeper into the endometrium. By the 7th day, the superficially implanted blastocyst has a primary endoderm (hypoblast) that resides on the blastocystic surface of the embryoblast.
Fertilization
Fertilization occurs when a sperm and an egg have fused together to form a zygote, which begins to divide as it moves towards the uterus.
Key Points
Fertilization is commonly known as conception. Once the fertilized gamete (ovum) implants itself in the uterine lining, pregnancy begins.
The fusion of male and female gametes ( sperm and ovum, respectively) usually occurs following the act of sexual intercourse. However, artificial insemination and in vitro fertilization have made achieving pregnancy possible without engaging in sexual intercourse.
The process of fertilization occurs in several steps and the interruption of any of them can lead to failure.
Prior to fertilization, sperm undergo a process of capacitation in response to conditions in the female reproductive tract, which include increases in motility and destabilization of the cell membrane that allows the head of the sperm to penetrate the egg.
Key Terms
- fertilization: The act of fecundating or impregnating animal or vegetable gametes.
- capacitation: A step spermatozoa undergo in the female reproductive track that renders them capable of fertilizing an oocyte.
- implantation: The embedding of the fertilized ovum into the uterine wall.
- Nondisjunction: Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division.
- zygote: A fertilized egg cell.
If pregnancy is considered to begin at the point of implantation, the process leading to pregnancy occurs earlier as the result of the female gamete, or oocyte, merging with the male gamete, or spermatozoon. In medicine, this process is referred to as fertilization; in lay terms, it is more commonly known as conception.
After the point of fertilization the fused product of the female and male gamete is referred to as a zygote or fertilized egg. For species that undergo internal fertilization, such as humans, the fusion of male and female gametes usually occurs following the act of sexual intercourse.
However, the advent of artificial insemination and in vitro fertilization have made achieving pregnancy possible without engaging in sexual intercourse. This approach may be undertaken as a voluntary choice or due to infertility.
Human fertilization: The sperm and ovum unite through fertilization, creating a zygote that (over the course of 8–9 days) will implant in the uterine wall, where it will reside over the course of 9 months.
The process of fertilization occurs in several steps and the interruption of any of them can lead to failure. At the beginning of the process, the sperm undergoes a series of changes, as freshly ejaculated sperm is unable or poorly able to fertilize.
The sperm must undergo capacitation in the female’s reproductive tract over several hours, which increases its motility and destabilizes its membrane. By destabilizing the membrane, the sperm prepares for the acrosome reaction, the enzymatic penetration of the egg’s tough membrane, the zona pellucida. The sperm and the egg cell (which has been released from one of the female’s two ovaries) unite in one of the two fallopian tubes.
The fertilized egg, known as a zygote, then moves toward the uterus, a journey that can take up to a week to complete until implantation occurs. Through fertilization, the egg is activated to begin its developmental process (progressing through meiosis II), and the haploid nuclei of the two gametes come together to form the genome of a new diploid organism.
Nondisjunction during the completion of meiosis or problems with early cell division in the zygote to blastula stages can lead to problems with implantation and pregnancy failure.
Cleavage of the Zygote
The process of cleavage is the step of embryogenesis where the zygote divides to produce a cluster of cells known as the morula.
Key Points
Following fertilization a series of rapid cell divisions occur that decrease the cells’ size with each subsequent division—this eventually produces a morula. The different cells derived from cleavage, up to the blastula stage, are called blastomeres.
For species such as humans, there is little yolk in eggs, and the divisions are relatively symmetrical, or holoblastic.
For other species, such as birds and reptiles, the presence of yolk dictates uneven meroblastic divisions that produce cells of uneven size and distribution.
The end of cleavage is known as the midblastula transition and coincides with the onset of zygotic transcription.
The cells of the morula are at first closely aggregated, but quickly become arranged into an outer or peripheral layer, the trophoblast, which does not contribute to the formation of the embryo proper, and an inner cell mass from which the embryo develops.
Key Terms
- cleavage: In embryology, this is the division of cells in the early embryo.
- trophoblast: The membrane of cells that forms the wall of a blastocyst during early pregnancy and provides nutrients to the embryo, and later develops into part of the placenta.
- zygote: A fertilized egg cell.
- morula: A spherical mass of blastomeres that forms following the splitting of a zygote; it becomes the blastula.
Cell division with no significant growth that produces a cluster of cells that is the same size as the original zygote, is called cleavage. At least four initial cell divisions occur, resulting in a dense ball of at least sixteen cells called the morula.
The different cells derived from cleavage up to the blastula stage are called blastomeres. Depending mostly on the amount of yolk in the egg, the cleavage can be holoblastic (total) or meroblastic (partial).
Cell cleavage: Early development is characterized by cleavage of the zygote, which refers to cell divisions that are not associated with significant growth of the embryo.
Holoblastic cleavage occurs in animals with little yolk in their eggs. These species, such as humans and other mammals, receive nourishment as embryos from the mother via the placenta or milk after birth.
On the other hand, meroblastic cleavage occurs in animals whose eggs have more yolk, such as birds and oviparous reptiles (although some viviparous reptiles also exist). Since cleavage is impeded by the vegetal pole, there is a very uneven distribution and size of cells. Cells are more numerous and smaller at the animal pole of the zygote than at the vegetal pole.
In holoblastic eggs, the first cleavage always occurs along the vegetal–animal axis of the egg, and the second cleavage is perpendicular to the first. From here, the spatial arrangement of blastomeres can follow various patterns, due to different planes of cleavage in various organisms.The end of cleavage is known as the midblastula transition and coincides with the onset of zygotic transcription.
In amniotes, the cells of the morula are at first closely aggregated. However, they quickly become arranged into an outer or peripheral layer, the trophoblast, and an inner cell mass. The trophoblast does not contribute to the formation of the embryo proper; the embryo develops from the inner cell mass.
Fluid collects between the trophoblast and the greater part of the inner cell mass, and thus the morula, is converted into the blastodermic vesicle (also called the blastocyst or blastula). The inner cell mass remains in contact with the trophoblast at one pole of the ovum. This is named the embryonic pole, since it indicates the location where the future embryo will develop.
In the case of monozygotic twins (derived from one zygote), a zygote divides into two separate cells (embryos) at the first cleavage division. Monozygotic twins can also develop from two inner cell masses.
A rare occurrence is the division of a single inner cells mass giving rise to twins. However, if one inner cell mass divides incompletely, the result is conjoined twins. Dizygotic twins is the development of two embryos from two different zygotes.
Blastocyst Formation
The blastocyst forms early in embryonic development and has two layers that form the embryo and placenta.
Key Points
The human blastocyst possesses an inner cell mass (ICM), or embryoblast, which subsequently forms the embryo, and an outer layer of cells, or trophoblast, which later forms the placenta.
The trophoblast surrounds the inner cell mass and a fluid-filled, blastocyst cavity known as the blastocoele or the blastocystic cavity. The trophoblast combines with the maternal endometrium to form the placenta in eutherian mammals.
Before gastrulation, the cells of the trophoblast become differentiated into two strata: the ectoderm of the chorion plays a role in the development of the placenta, and the endoderm differentiates and quickly assumes the form of a small sac, called the yolk sac.
The embryoblast is the source of embryonic stem cells and gives rise to all later structures of the adult organism.
The floor of the amniotic cavity is formed by the embryonic disk, which is composed of a layer of prismatic cells, and the embryonic ectoderm, which is derived from the inner cell mass and lies in opposition to the endoderm.
Key Terms
- embryonic disk: The floor of the amniotic cavity is formed by the embryonic disk (or disc) that is composed of a layer of prismatic cells called the embryonic ectoderm. It is the part of the inner cell mass from which the embryo is developed.
- blastocyst: An early form in the development of an embryo that consists of a spherical layer of cells filled with fluid.
- gastrulation: The stage of embryonic development when a gastrula is formed from the blastula by the inward migration of cells.
- eutherian: Refers to all species of which the female gives birth to live young that receive prenatal nourishment via the placenta.
In humans, the blastocyst is formed approximatelyy five days after fertilization. This stage is preceded by the morula. The morula is a solid ball of about 16 undifferentiated, spherical cells. As cell division continues in the morula, the blastomeres change their shape and tightly align themselves against each other. This is called compaction and is likely mediated by cell surface adhesion glycoproteins.
The blastocyst possesses an inner cell mass (ICM), or embryoblast, which subsequently forms the embryo, and an outer layer of cells, or trophoblast, which later forms the placenta. The trophoblast surrounds the inner cell mass and a fluid-filled, blastocyst cavity known as the blastocoele or the blastocystic cavity.
The embryoblast is the source of embryonic stem cells and gives rise to all later structures of the adult organism. The trophoblast combines with the maternal endometrium to form the placenta in eutherian mammals.
Blastocyst: The blastocyst possesses an inner cell mass from which the embryo will develop, and an outer layer of cells, called the trophoblast, which will eventually form the placenta.
Before gastrulation, the cells of the trophoblast become differentiated into two strata. The outer stratum forms a syncytium, which is a layer of protoplasm studded with nuclei that shows no evidence of subdivision into cells (termed the syncytiotrophoblast).
The inner layer, the cytotrophoblast or layer of Langhans, consists of well-defined cells. As already stated, the cells of the trophoblast do not contribute to the formation of the embryo proper; they form the ectoderm of the chorion and play an important part in the development of the placenta.
On the deep surface of the inner cell mass, a layer of flattened cells, called the endoderm, is differentiated and quickly assumes the form of a small sac, called the yolk sac. Spaces appear between the remaining cells of the mass and, by the enlargement and coalescence of these spaces, a cavity called the amniotic cavity is gradually developed.
The floor of this cavity is formed by the embryonic disk, which is composed of a layer of prismatic cells called the embryonic ectoderm. This layer is derived from the inner cell mass and lies in opposition to the endoderm.
Implantation
Implantation is the very early stage of pregnancy at which the embryo adheres to the wall of the uterus and begins to form the placenta.
Key Points
At this stage of prenatal development the embryo is a blastocyst. In humans, implantation of a fertilized ovum occurs between 6 to 12 days after ovulation.
In preparation for implantation, the blastocyst sheds its outside layer, the zona pellucida, and is replaced by a layer of underlying cells called the trophoblast. The trophoblast will give rise to the placenta after implantation.
During implantation, the trophoblast differentiates into two distinct layers: the inner cytotrophoblast, and the outer syncytiotrophoblast. The syncytiotrophoblast then implants the blastocyst into the endometrium by forming finger-like projections into the uterine wall called chorionic villi.
Key Terms
- endometrium: The mucous membrane that lines the uterus in mammals and in which fertilized eggs are implanted.
- trophoblast: The membrane of cells that forms the wall of a blastocyst during early pregnancy and provides nutrients to the embryo and later develops into part of the placenta.
- human chorionic gonadotropin (hCG): In molecular biology, human chorionic gonadotropin (hCG) is a hormone produced during pregnancy that is made by the developing placenta after conception, and later by the placental component.
- implantation: The embedding of the blastocyst to the uterine wall.
Implantation is the very early stage of pregnancy during which the embryo embeds into the wall of the uterus. At this stage of prenatal development, the embryo is a blastocyst.
It is by this adhesion that the fetus receives oxygen and nutrients from the mother to be able to grow. In humans, implantation of a blastocyst occurs between 6 to 12 days after ovulation.
In preparation for implantation, the blastocyst sheds its outside layer, the zona pellucida, which binds sperm during fertilization. The zona pellucida degenerates and decomposes, and is replaced by a layer of underlying cells called the trophoblast.
The trophoblast will give rise to the placenta after implantation. During implantation, the trophoblast differentiates into two distinct layers: the inner cytotrophoblast, and the outer syncytiotrophoblast.
Chorionic villi: During implantation, extensions of the trophoblast, the syncytiotrophoblasts, embed within the endometrium and form chorionic villi.
The syncytiotrophoblast then implants the blastocyst into the endometrium of the uterus by forming finger-like projections into the uterine wall called chorionic villi. The chorionic villi grow outwards until they come into contact with the maternal blood supply.
The chorionic villi will be the border between maternal and fetal blood during the pregnancy, and the location of gas and nutrient exchange between the fetus and the mother. The creation of chorionic villi is assisted by hydrolytic enzymes that erode the uterine epithelium.
The syncytiotrophoblast also produces human chorionic gonadotropin (hCG), a hormone that notifies the mother’s body that she is pregnant and prevents menstruation by sustaining the function of the progesterone-producing corpus luteum within the ovary.
Human chorionic gonadotropin is the hormone that is detected by pregnancy tests, as it is found in the maternal bloodstream and urine.
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