FIRST WEEK OF DEVELOPMENT

From Ovulation to Implntation

By
Aiah Lebbie
M.B.Ch.B, FCS (ECSA)
 Ovarian/Menstrual/Sex Cycle
• The menstrual cycle begins when a girl reaches the age of
puberty
• It is the reproductive cycle that produces eggs for
fertilization
• During the menstrual cycle the uterus (endometrium)
prepares itself for implantation of a fertilized egg
• if fertilization does not occur the uterine lining is shed from
the body in a process known as menstruation or a "period".
• On average the menstrual cycle lasts between 28-35 days
• Day 1 of the cycle begins on is the first day of bleeding
(bleeding can last for 3-7 days) and the cycle ends just
before the next menstrual period
• The cycle can be divided into three phases
• follicular (before the egg is released
• ovulatory (egg is released)
• luteal (after release of the egg)
 Follicular Phase
• This phase begins on the first day of bleeding
• The key aspect of this phase is the
development of follicles in the ovaries
• Controlled by FSH 
• 15 to 20 primary (preantral) stage follicles are
stimulated to grow under the influence of FSH
• only one of these follicles reaches full
maturity, and only one oocyte is discharged
• the others degenerate and become atretic
• This process is repeated in the next cycle
• FSH also stimulates maturation of follicular
(granulosa) cells surrounding the oocyte
• growth differentiation factor 9 (GDF9), a
member of the transforming factor beta
mediate proliferation of the follicular cells
• The granulosa and thecal cells produce
estrogens that cause
– the uterine endometrium to enter the follicular or
proliferative phase
– thinning of the cervical mucus to allow passage of
sperm
– stimulate the pituitary gland to secrete LH.
• At midcycle, there is an LH surge that
• elevates concentrations of maturation-
promoting factor, causing the primary

• stimulates production of progesterone by

follicular stromal cells
• causes follicular rupture and ovulation 
 Ovulation
• Preovulatory changes seen include :
– Rapid growth of the secondary follicle to a
diameter of 25 mm under the influence of FSH
and LH
– LH surge →
– primary oocyte to complete meiosis I to become
secondary oocyte
– follicle to enter the preovulatory stage
– Meiosis II is also initiated, but the secondary
oocyte is arrested in metaphase approximately 3
hours before ovulation
• increases collagenase activity → digestion of
collagen fibers surrounding the follicle
• the surface of the ovary begins to bulge
locally, and at the apex, an avascular spot, the
stigma, appears
• Increase Prostaglandin levels → local muscular
contractions in the ovarian wall → extrude the
oocyte in a process called ovulation
• Ovulation = oocyte + surrounding follicular cell
in the region of cumulus oophorus break loose
and float on the surface of the ovary
 REQUIRES
NO FSH FSH
• Some of the cumulus oophorus cells then
rearrange themselves around the zona
pellucida to form the corona radiata
 Clinical Correlates
• Mid Cycle pain → occurs at the time of
ovulation and result from the bulging oocyte
stretching the ovarian capsule
• rise in basal temperature →monitored to
determine when release of the oocyte occurs
• Failure to ovulate may result from a low
concentration of gonadotropins
• Can be fixed by administering agents which
stimulate gonadotropin release → multiple
pregnancy
 Formation of Corpus Luteum
• Corpus luteum develops from two group of cells
– granulosa cells remaining in the wall of the ruptured
follicle
– cells from the theca interna
• These cells become vascularized by surrounding
vessels
• Under the influence of LH, these cells develop
yellowish pigment and change into lutean cells,
which form the corpus luteum
 Is the Corpus Luteum Important
• The corpus luteum secrete progesterone
• Progesterone + estrogen hormones → uterine
mucosa to enter the progestational or
secretory stage in preparation for implantation
of the embryo
hypertrophy and accumulation of lipid in granulosa and
theca interna cells forms the Corpus Luteum
Oocyte Transport
• The sweeping movement of the fimbrae over
the ovary collect the ovum at ovulation
together with the granulosa cell surrounding
the oocyte
• The ovum in transported in the tube by the
rhythmic contraction of the tube together
with movement of cilia lining the epithelium
of the tube
• Once in the tube, cumulus cells withdraw their
cytoplasmic processes from the zona pellucida
• Fertilization takes place in the ampulla of the
tube
• In humans, the fertilized oocyte reaches the
uterine lumen in approximately 3 to 4 days
• If fertilization does not occur
• the corpus luteum continues its development
for approximately 9 days after ovulation
• degeneration of lutean cells occur to forms a
mass of fibrotic scar tissue, the corpus
albicans
• progesterone production decreases,
precipitating menstrual bleeding
• If the oocyte is fertilized
• syncytiotrophoblast of the developing embryo
secretes human chorionic gonadotropin (hCG)
• hCG prevent degeneration of the corpus
luteum
• The corpus luteum continues to grow and
forms the corpus luteum of pregnancy
• The corpus luteum continues to secrete
progesterone until the end of the fourth
month
• trophoblastic component of the placenta takes
over progesterone production → adequate for
maintenance of pregnancy
• Corpus luteum then regresses slowly
• Removal of the corpus luteum of pregnancy
before the fourth month usually leads to
abortion
 Fertilization
• Male gamete + Female gamete = Zygote
• Takes place in the ampullary region of the
uterine tube
• Spermatozoa may remain viable in the female
reproductive tract for several days(up to 5
days)
• Only 1% of sperm deposited in the vagina
enter the cervix, where they may survive for
many hours
Movement of sperm from the cervix to the isthmus
of uterine tube → self propulsion ± assisted by cilia
• Sperm takes 2 to 7 hours to reach the tube
• become less motile after reaching the isthmus
and cease their migration
• At ovulation, sperm again become motile and
swim to the ampulla, where fertilization
usually occurs
• For the Spermatozoa to be able to fertilize the
oocyte, it must under the following changes :
1. capacitation
2. acrosome reaction to acquire this capability
 Capacitation
• is a period of conditioning in the female
reproductive tract
• lasts approximately 7 hours in humans
• occurs in the uterine tube and entails
– epithelial interactions between the sperm and
mucosal surface of the tube
– Removal of glycoprotein coat and seminal plasma
proteins overlying the acrosomal region of the
spermatozoa
• Only capacitated sperm can pass through the
corona cells and undergo the acrosome reaction
 Acrosome Reaction
• occurs after binding of the sperm to the zona
pellucida of the oocyte → induced by zona proteins
• release of proteolytic enzymes needed to penetrate
the zona pellucida, including acrosin- and trypsin-
like substances
• The phases of fertilization include
• phase 1 → penetration of the corona radiata
• phase 2 → penetration of the zona pellucida
• phase 3 → fusion of the oocyte and sperm cell
membranes
Phase 1: Penetration of the Corona Radiata

• 200 to 300 million spermatozoa are deposited

in the female genital tract
• only 300 to 500 reach the site of fertilization
• Only one of fertilizes the egg
• ? the others aid the fertilizing sperm
• Capacitated sperm pass freely through corona
cells
Phase 2: Penetration of the Zona Pellucida

• The zona pellucida is a glycoprotein shell

surrounding the egg
• facilitates and maintains sperm binding to oocyte
• induces the acrosome reaction → entry of the
sperm
• ZP3 mediates binding and acrosome reaction
• when the head of the sperm comes in contact with
the oocyte surface → release of lysosomal
enzymes from cortical granules lining the plasma
membrane of the oocyte
• These enzymes alter properties of the zona
pellucida (zona reaction) to prevent sperm
penetration
• inactivate species-specific receptor sites for
spermatozoa on the zona surface
 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 plasma membranes of the
sperm and egg fuse
• fusion occurs between the oocyte membrane
and the membrane that covers the posterior
region of the sperm head
• both the head and tail of the spermatozoon enter
the cytoplasm of the oocyte leaving the plasma
membrane behind on the oocyte surface
• the egg responds in three ways to the entry of the
sperm
– Cortical reactions → lysosomal enzymes released from
cortical granuules
– the oocyte membrane becomes impenetrable to other
spermatozoa
– the zona pellucida alters its structure and composition to
prevent sperm binding and penetration
• These reactions prevent polyspermy
Resumption of the second meiotic division

• The oocyte finishes its second meiotic division

immediately after entry of the spermatozoon
producing two daughter cells
1. second polar body
2. definitive oocyte
– chromosomes (22 plus X) arrange themselves in a
vesicular nucleus known as the female pronucleus
 Metabolic activation of the egg
• The activating factor is probably carried by the
spermatozoon
• Post fusion activation may be considered to
encompass the initial cellular and molecular
events associated with early embryogenesis
• The spermatozoon moves forward and lies close
to the female pronucleus
• nucleus becomes swollen and forms the male
pronucleus
• the tail detaches and degenerates
• Morphologically, the male and female pronuclei
are indistinguishable
• eventually, they come into close contact and
lose their nuclear envelopes
• The male and female pronuclei (both haploid)
grow and replicate their 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
• This provide 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
 Results of fertilization
• Restoration of the diploid number of chromosomes,
half from the father and half from the mother
• Determination of the sex of the new individual
– An X-carrying sperm produces a female (XX) embryo
– 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 within24 hours after ovulation
 Clinical Correlates
• Contraceptive Methods
• The contraceptive methods in use usually
• interrupt a step in the female sex cycle or a
• step in the first week of development from
0vulation to implantation
 Barrier Techniques
• Prevent fertilization by preventing the sperm
from reaching the female genital tract and thus
prevent fertilization :
• male condom, made of latex, often containing
chemical spermicides, which fits over the penis
• female condom, made of polyurethane, which
lines the vagina
• Other barriers placed in the vagina → diaphragm,
the cervical cap, and the contraceptive sponge
 The contraceptive Pill
• is a combination of estrogen and the
progesterone analogue progestin
• inhibit ovulation but permit menstruation
• prevent releaseof FSH and LH from the
pituitary
• pills are taken for 21 days and then stopped to
allow menstruation
• the cycle is repeated
 Depo-Provera
• is a progestin compound
• Can be implanted subdermally or injected
intramuscularly
• Subdermal implantion prevents ovulation for
up to 5 years
• Intramuscular injection prevents ovulation for
up to 23 months
 The Male “Pill”
• has been developed and tested in clinical
trials.
• contains a synthetic androgen that prevents
both LH and FSH secretion
• stops sperm production (70% to 90% of men)
• reduces it to a level of infertility
 The intrauterine device (IUD)
• is placed in the uterine cavity. Its mechanism for
preventing pregnancy is not clear
• may entail direct effects on sperm and oocytes
• or inhibition of preimplantation stages of
development
• Vasectomy and tubal ligation are effective means
of contraception
• both procedures are reversible, although not in
every case
 Infertility
• Affect 15% to 30% of couples
• Male infertility can be caused by
• oligospermia
• azoospermia
• poor motility of sperm
• Normally, ejaculate has
 a volume of 3 to 4 mls
 ontain approximately 100 million sperm per ml
 20 million sperm per ml or 50 million sperm per total ejaculate
are usually fertile
• Infertility in a woman may be due to :
• occluded uterine tubes ← pelvic inflammatory
disease)
• hostile cervical mucus
• immunity to spermatozoa
• absence of ovulation
Assisted Reproductive Technology (ART)

• In vitro fertilization (IVF) of human ova and

embryo transfer
• Gamete intrafallopian transfer (GIFT)
• zygote intrafallopian transfer (ZIFT),
 Cleavage

• 12- to 16-cell stage is • blastomeres are

reached at approxly 3 days surrounded by the zona
• late morula stage is reached pellucida → disappears at
at approximately 4 days the end of the fourth day
• Cleavage is a series of mitotic divisions →
increase the numbers of cells
• the cells become smaller with each cleavage
and are known as blastomeres
• Initially the cells are loosely arranged
• after the third (8 cell stage) cleavage,
blastomeres become tightly held together by
tight junctions → Compaction
• Compaction → differentiate inner cells from
outer cells
• uncompacted state → • Compaction →
outlines of each cellular outlines are
blastomere are distinct indistinct
 Morula
• Approximately 3 days after fertilization, cells
of the compacted embryo divide again to form
a 16-cell morula
• Inner cell of the morula → Inner cell mass
– gives rise to tissues of the embryo proper
• surrounding cells compose the Outer cell mass
– forms the Trophoblast → contribute to the
placenta
 Blastocyst Formation
• Morula → blastocyst
• Fluid spaces form in the inner cell mass and
coalesce to form a single cavity
• A morula with with this fluid filled cavity is
called a Blastocyst
• Cells of the inner cell mass = embryoblast
• Located at one pole
• outer cell mass =Trophoblast
 Implantation
• Disappearance of zona pellucida → implantation begins
• trophoblastic cells over the embryoblast pole begin to
penetrate between the epithelial cells of the uterine
mucosa on about the sixth day
• studies → L-selectin on trophoblast cells and its
carbohydrate receptors on the uterine epithelium
mediate initial attachment of the blastocyst to the
uterus
• Integrins expressed by trophoblast and extracellular
matrix molecules laminin and fibronectin → enhance
attachment and invasion of the uterine lining by the
blastocyst
• 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
 Clinical Application
• inner cell mass → Embryonal Stem Cell

pluripotent and can cure

many diseases
• Adult Stem Cells are multipotent and not
pluripotent but can also be uselful in curing
certain diseases
 Abnormal Zygotes
• Up to 50% of pregnancies end in spontaneous
abortion
• half of these losses are a result of chromosomal
abnormalities
• Without this phenomenon, approximately 12%
instead of 2% to 3% of infants would have birth
defects.
 Uterus at Time of Implantation
• The uterus has three layers → endometrium,
myometrium and perimetrium
• During the menstrual cycle, the endometrium
passes through three stages
• follicular or proliferative phase
• secretory or progestational phase
• menstrual phase
• The Proliferative Phase
• begins at the end of the menstrual phase
• Controlled by estrogen
• parallels growth of the ovarian follicles
• The secretory phase
• begins approximately 2 to 3 days after
ovulation
• Influenced by progesterone produced by the
corpus luteum
• The Menstrual Phase
• If fertilization does not occur partial shedding
of the endometrium occurs
• This shedding marks the beginning of the
menstrual phase
• If fertilization does occur, the endometrium
– assists in implantation
– contributes to formation of the placenta
• Implantation occurs in the secretory phase
• uterine glands and arteries become coiled and
the tissue becomes succulent
Implantation of
blastocyst Progesterone
production
Development of Increased secretory
Corpus luteum Activity of endometrium
• If the oocyte is not fertilized
– venules and sinusoidal spaces gradually become
packed with blood cells
– extensive diapedesis of blood into the tissue is seen
– menstrual phase → blood escapes from superficial
arteries
– small pieces of stroma and glands break away
– the compact and spongy layers are expelled from
the uterus
– the basal layeris retained and will regenerate the
other layers in the proliferative phase