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.
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
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.
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
Ovulation
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.
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 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.
OOCYTE
TRANSPORT
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.
CORPUS
ALBICANS
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
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
(a)capacitationand
(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.
PHASE 1:
PENETRATION OF THE CORONA RADIATA
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.
PHASE 2:
PENETRATION OF THE ZONA PELLUCIDA
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.
PHASE 3:
FUSION OF THE OOCYTE AND
SPERM CELL
MEMBRANES
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.
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. 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.
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 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.
