Dr. Raymond Colello
EMBRYOLOGY:
Fertilization and Implantation
Recommended Reading: Larsen, pp. 1-51
Langman, pp. 3-52
Moore, pp. 4-37
OBJECTIVES: Following the lecture the student should be able to:
1.) Describe the chronology of events taking place during the first 8 weeks of
embryonic development.
2.) Describe the origin and fate of the primordial germ cells.
3.) Compare and contrast spermatogenesis and oogenesis.
4.) Describe the periods of susceptibility to teratogens.
5.) Describe how hormonal regulation effects endometrium development and
ovarian activity during a menstrual cycle.
6.) Define the functions of the corpus luteum, zona pellucida, acrosomal enzymes,
trophoblast cells and the chorionic villi.
7.) Define spermatogonia, primary spermatocyte, secondary spermatocyte,
oogonia, primary oocyte, secondary oocyte and ovum.
II.) Gametogenesis and Fertilization
A.) General Embryological Terms in Gametogenesis and Fertilization
1.) Oocyte: female sex cell produced in the ovaries
2.) Sperm: male sex cell produced in the testes
3.) Gametes: male or female sex cells
4.) Zygote: cell formed from the union of the oocyte and sperm
5.) Fertilization: process by which male and female gametes fuse
6.) Cleavage: mitotic cell division of the zygote
7.) Morula: cleavage of zygote to 32 or more cells
8.) Trophoblast: outer cell mass of morula giving rise to the placenta
9.) Blastocyst: the morula forming a fluid-filled central cavity
The development of a human begins with the formation and differentiation of the male and
female sex cells or gametes, which will fuse during fertilization to initiate the embryonic
development of a new individual. In humans, the cell line that gives rise to the gametes are
called the primordial germs cells which originate on the yolk sac at and 4 weeks of embryonic
development and migrate to the posterior body wall or presumptive gonadal region (fig.1).
Fig. 1: The primordial germ cells differentiate in the endodermal layer of the yolk sac at 4 to 6 weeks of
development and migrate to the dorsal body wall (A). Between the 6 and 12weeks, the primordial germ cells
induce formation of the genital ridges (B). (taken from Larsen, "Human Embryology", 1993)
Here they proliferate to form compact strands of tissue called the primitive sex cords, which
swell to become the genital ridges, or the primordial gonads. Within the developing gonads,
the primordial germ cells differentiate into precursor cells called spermatogonia in the male
and oogonia in the female, both of which are diploid (contain a complement of 23 pairs of
chromosomes or a total of 46 chromosomes). During gametogenesis, these cells undergo
meiosis, so that the gametes produced are haploid, containing only 23 chromosomes (fig. 2).
Fig. 2: Nuclear maturation of germ cells in meiosis in the male and female. In the male, the primordial germ
cells remain dormant until puberty, when they differentiate into spermatogonia and commence mitosis.
Throughout adulthood, the spermatogonia produce primary spermatocytes, which undergo meiosis and
spermatogenesis. In the female, the primordial germ cells differentiate into oogonia, which undergoes mitosis and
then commence meiosis as primary oocytes during fetal life. The primary oocytes remain arrested in prophase I
until stimulated to resume meiosis during the menstrual cycle. (taken from Larsen, "Human Embryology", 1993)
The timing of gametogenesis differs in the two sexes. In males, the primordial germ cells
remain dormant until puberty, when the seminiferous tubules mature and the germs cells
differentiate into spermatogonia. These undergo meiosis, reducing their chromosome numbers
by half, and mature into spermatozoa. In females, the primordial germ cells go through a
series of mitotic division early in fetal development, differentiate into oogonia, and then all
begin meiosis by the fifth embryonic month.
B.) Spermatogenesis and Oogenesis
In males, increased secretion of testosterone by the testis at puberty stimulates the growth of
the testis and the maturation of the seminiferous tubules. This, in turn, induces spermatogenesis
whereby the dormant primordial germ cells divide several times and then differentiate into
spermatogonia (fig.3).
In females, the total number of primary oocytes that individual will ever possess is produced
in the ovaries by 5 months of fetal life. By the 3 rd month of development, some oogonia give
rise to primary oocytes that enter prophase of the 1st meiotic division. At birth, all the oogonia
have been transformed to dormant primary oocytes that are surrounded by a single layer of
follicle cells, thus forming the primary follicle. These cells will then lay dormant until after
puberty when they resume development in response to hormonal signals, which initiate the
menstrual cycle. The total number of primary oocytes at birth is roughly 1 million, with these
numbers declining to 400,000 at the time of puberty. Fewer than 500 will be released during
the reproductive years of a woman (fig. 4).
Fig. 3: (A) A schematic section through the seminiferous tubule wall. The spermatogonium just under the outer
surface of the tubular wall (basal side) undergoes mitosis to daughter cells, which may either continue to divide by
mitosis or may commence meiosis as primary spermatocytes. The differentiating cells translocate to the tubular
lumen. (B) From puberty sperm are constantly produced in the seminiferous tubules and passed through the tubules
and into the epididymis, were they are stored (taken from Larsen, "Human Embryology", 1993).
Fig. 4: Depiction of folliculogenesis and ovulation in the ovary (taken from Larsen, "Human Embryology", 1993).
C.) Ovulation
At puberty, the female begins to undergo regular monthly cycles, called menstrual
cycles, which are controlled by the release of hormones from the hypothalamus and anterior
pituitary gland. The release of gonadotrophin-releasing hormone by the hypothalamus
stimulates cells of the pituitary gland to release the gonadotrophins, follicle-stimulating
hormone (FSH) and luteinizing hormone (LH), which stimulate and control cyclic changes in
the ovary (fig.5), leading to ovulation. In fact, the resumption of meiosis and ovulation are
stimulated by an ovulatory surge of FSH and LH.
Fig. 5: (A) Schematic drawing of changes taking place in the uterine mucosa (endometrium) during a regular
menstrual cycle in which fertilization fails to occur. Note the corresponding changes in the ovary (taken from
Larsen, "Human Embryology", 1993). (B) The ovaries are covered by a layer of cells. The cells which are destined
to become ova (eggs) pass into the substance of the ovaries, where they are surrounded by a follicle membrane.
Each month a single follicle matures, bursts in one ovary's surface and is released. If fertilized, the corpus luteumwhich develops at the site of the egg's follicle-grows and secretes hormones that maintain pregnancy (taken from
"Atlas of Anatomy", Marshall Cavendish books, 1991).
The thickening of the endometrium (womb lining) is caused by hormones, which are released at
the end of menstruation. During this time a follicle is maturing in the ovary as a result of FSH
release and begins to produce estrogen, which acts to control the cycle of uterine endometrium.
After the egg is released, through the stimulation of LH hormone, a mass of cells (the corpus
luteum) forms in the empty follicle. These cells secrete the hormone, progesterone, which
causes the endometrium to thicken further. If pregnancy occurs, the corpus luteum persists and
continues to maintain the womb lining. If it does not, the corpus luteum shrinks and hormone
release drops. As a result, the womb lining is shed-this being known as the menstrual period
(Fig. 6).
Fig. 6: Ovarian, endometrial and hormonal events of the menstrual cycle.
C.) Fertilization
Fertilization takes place in the ampullary region of the uterine tube, the region of the
tube located close to the ovary (fig. 7). Spermatozoa, however, are not capable of fertilizing an
egg until they have undergone a process called capacitation, whereby the glycoprotein coat and
the seminal proteins are removed from the sperm's acrosome (head of the sperm). This change
allows the acrosome to release enzymes required to penetrate the glycoprotein shell of the
oocyte, the zona pellucida. Concurrently, the oocyte is released from the ovary during
ovulation and "swept" into the opening of the uterine tube by the finger-like fimbriae of the tube
lying adjacent to the ovary (fig.7). The fusion of the spermatozoan cell membrane with the
oocyte membrane causes the oocyte to resume meiosis (fig. 8). Once penetration of the zona
pellucida has occurred, the cell membranes of the sperm and oocyte can fuse, forming zygote.
This represents the zero point of embryonic development.
D.) Cleavage
The zygote now undergoes a series of mitotic divisions, resulting in a rapid increase in the
number of cells, now called blastomeres (Fig. 9). This process of cleavage normally occurs as
the zygote passes through the tube and toward the uterus (fig.7C). Cleavage, however,
subdivides the zygote without increasing its size. By 3 days post-fertilization, the embryo
consists of 6-12 cells, and by 4 days, 16-32 cells. By the 32-cell stage, the embryo is now
termed a morula. This structure gives rise to both the embryo proper and the placenta and
related structures. The cells that will make these structures begin to segregate during cleavage
so that some blastomeres lie in the center of the morula (called the inner cell mass) and some
Fig. 7: Cleavage and transport down the oviduct. (taken from”Atlas of anatomy”,Marshall Cavendish books, 1991).
Fig. 8: (A) Fertilization. Penetration of a spermatozoa into the oocyte. (taken from Larsen, "Human Embryology",
1993).
lie in the periphery (called the outer cell mass). The inner cell mass gives rise to the embryo
proper and is therefore called the embryoblast while the outer cell mass gives rise to the
placenta and is therefore called the trophoblast. By the 4-day post-fertilization, the morula
develops a fluid-filled cavity and is transformed into a blastocyst. This structure frees itself for
its outer shell, the zona pellucida, and begins to implant itself into the uterine wall on about day
6. If an embryo implants, the hormone human chorionic gonadotrophin is secreted to support
the corpus luteum and thus maintain the supply of progesterone. Due to the burrowing
capabilities of the blastocyt, occasionally implantation can occur in abnormal sites leading to
ectopic pregnancies (fig. 10). This can be life threatening since the blastocyst can erode
arteries and the blood supply of these sites. Surgical intervention may be required to remove
the developing embryo.
Fig. 9: Cleavage of the zygote during the first 5-days following fertilization.
Fig. 9: Drawing to show abnormal implantation sites of the blastocyst (taken from "Medical Embryology", Sadler,
1995).
At the beginning of the second week, the embryoblast splits into two layers, the epiblast
or primary ectoderm and the hypoblast or primary endoderm (fig. 10). A cavity, called the
amniotic cavity, then develops within the epiblast as a layer of cells derived from the epiblast
thins to become the anmiotic membrane. The remainder of the epiblast and hypoblast now
constitute a bilaminar disc lying between the amniotic cavity and the blastocyte cavity. The
cells of this germ disc develop into the embryo proper.
E.
Implantation
At 7 days post fertilization, the blastocyst contacts the uterine emdometrium and begins
to implant. Specifically, cells of the tropoblast called the syncytiotrophoblast actively
invade the endometrium and pulls the blastocyst into the uterine wall (fig. 10).
Fig. 10: The implantation of the blastocyst and the formation of the bilaminar disc (taken from Larsen, "Human
Embryology", 1993).