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GAMETOGENESIS AND FIRST WEEK OF DEVELOPMENT

Dr. Juan B. Fernndez Prez

Langmans 2012, Chs. 2 & 3, p. 10 42
I.

GAMETOGENESIS
a. The purposes of gametogenesis are three-fold:
i. Reducing the number of chromosomes (46) to half (23).
ii. Exchange of genetic material, which is achieved during prophase I.
iii. Alteration of the shape of germ cells.
b. Primordial germ cells (PGCs) are formed in the epiblast during second
week and move to the yolk sac. In the 4th week migrate from the yolk sac to
the developing ovaries and testes where they arrive at the end of the fifth
week and differentiate there as oogonia and spermatogonia.

Please review yourself mitosis and meiosis from pages 11-13 in Langmans Twelfth Ed.
c. Oogenesis, the sequence of events by which oogonia are transformed into
ova is as follows:
i. Oogonia undergo many mitotic divisions. By the end of the 3rd
month oogonia differentiate into primary oocytes. The primary
oocytes now enter the prophase I, and then almost immediately
become dormant (dictyotene stage or diplotene).
1. By 5th intrauterine month primary oocyte peaks 7 million. At
this time cell death begins, and becomes atretic.
2. By 7th intrauterine month all surviving primary oocytes have
entered prophase of meiosis I, and most are individually
surrounded by a layer of flat follicular epithelial cells Primordial follicle.
3. At Birth only 600,000 - 800,000 - primary oocytes remain
due to degeneration.
4. At puberty there are 40,000 primary oocytes. Many follicles
(15-20) start to mature each month, as result of hormonal
stimulation, but only one reaches maturity (if fertilization
occurs). Fewer than 500 will be ovulated.
5. This arrested state is produced by oocyte maturation
inhibitor (OMI) a small peptide secreted by follicular cells.
ii. Primary oocytes meiotic division is finally completed a few hours
before ovulation. These first meiotic division results in a large
secondary oocyte and a small first polar body (both cells are
haploid but 2n).
iii. The secondary oocyte immediately undergoes the second meiotic
division but about 3 hours before ovulation enters meiotic arrest
(metaphase II).
iv. The second maturation division is completed only if the oocyte is
fertilized; otherwise the cell degenerates approximately 24 hours
after ovulation.
v. Development of the follicle:
1. While the primary oocyte increases in size, the surrounding
follicular cells change to produce a stratified cuboidal
epithelium of granulosa cells and are called the primary
follicle.

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2. Surrounding stromal cells form the theca folliculi.

Granulosa cells and oocyte secrete a glycoprotein, forming
the zona pellucida.
3. Theca folliculi become organized into an inner layer of
secretory cells the theca interna, and an outer layer of
connective tissue, fibrous capsule, is the theca externa.
4. Fluid filled spaces appear between the granulosa cells,
coalesce and form the antrum (secondary follicle).
vi. Granulosa cells surrounding the oocyte remain intact and form the
cumulus oophorus. During ovulation oocyte surrounding cells are
called the corona radiata.
vii. Mature follicle, which may be 10 mm or more in diameter, is known
as the tertiary, vesicular or Graffian follicle.
viii. Ovulation
1. Is stimulated by a surge of LH and FSH. Expulsion of the
ovum from the Graffian follicle involves local edema,
ischemia, collagen breakdown, fluid pressure, and smooth
muscle activity in rupturing the follicular wall.
2. The ovulated egg is swept into the uterine tube and
transported through it by ciliary action and smooth muscle
contractions.
ix. Hormonal control
1. The releasing or inhibiting factors from the hypothalamus
acting on the adenohypophysis cause the release of pituitary
hormones (FSH, LH). The pituitary hormones stimulate the
ovarian follicle to produce estrogens. In pregnancy, the
remains of the follicle (corpus luteum) continue to produce
progesterone, which maintains the early embryo until the
placenta begins to produce sufficient hormones to maintain
pregnancy until the end of the fourth month. Removal of the
corpus luteum of pregnancy before the 4th month usually
leads to abortion.
2. Under the influence of estrogens and then progesterone, the
endometrium of the uterus builds up in preparation to receive
the embryo. In the absence of fertilization and with the
subsequent withdrawal of hormone support, the
endometrium breaks down and is shed (menstruation). The
corpus luteum reaches maximum development 9 days after
ovulation. Degeneration of lutean cells forms a fibrotic scar
tissue, the corpus albicans.
3. FSH stimulates the uterine endometrium in follicular or
proliferative phase, thinning of the cervical mucus to allow
passage of sperm.
4. LH surge at midcycle causes oocytes to complete meiosis I
and initiate meiosis II, stimulate production of progesterone
and causes follicular rupture and ovulation.
a. The oocyte is arrested in metaphase II
approximately 3 hours before ovulation.
b. LH increase collagenase activity resulting in
digestion of collagen fibers surrounding the follicle.

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c. Prostaglandin levels increases and cause local

muscular contractions in the ovarian wall extruding
the oocyte (ovulation). Cumulus oophorus cells
rearrange around the zona pelludica fo form the
corona radiate.
d. Granulosa cell develop a yellowish pigment, called
lutein cells, secrete progesterone. The uterine
mucosa enters progestacional or secretoy phase.
d. Spermatogenesis. The transformation of spermatogonia into spermatozoa
involves two distinct stages:
(1) cell growth and multiplication
(spermatocytogenesis) and (2) cell metamorphosis (spermiogenesis).
i. Primordial germ cells remain dormant from the 6th week of
embryonic development until puberty. At puberty germ cells
differentiate into spermatogonia.
Successive waves of
spermatogonia undergo meiosis and mature into spermatozoa
continuously until death.
ii. Shortly before puberty the sex cords acquire a lumen and become the
seminiferous tubules, the primordial germ cells give rise to
spermatogonia, of two types: type A spermatogonia - divide by
mitosis, and type B spermatogonia - give rise to primary
spermatocytes.
iii. Primary spermatocytes (2n) are followed by rapid completion of
meiosis I, and formation of secondary spermatocytes (2n, haploid).
These cells begin immediately with the second meiotic division to
form spermatids (n, haploid).
iv. From the time type A cells leave the stem cell population fo
formation of spermatids, cytokinesis is incomplete, such that
successive germ cell generations are joined by protoplasmic bridges.
These cells remain embedded in deep recesses of Sertoli cells or
sustentacular cells (derived from the superficial epithelium of the
testis) throughout their development, providing support and
protection for the germ cells.
v. Spermiogenesis, transformation of spermatids into spermatozoa.
Include:
1. formation of the acrosome from the golgi apparatus;
2. condensation of the nucleus;
3. formation of the neck, middle piece and tail; and
4. Shedding of most of the cytoplasm.
vi. Each cycle of spermatogenesis takes about 64 days (74 Langmans),
mitosis, 16 days, meiosis I, 8 days, meiosis II,16 days and
spermiogenesis, 24 days. Approximately 300 million sperm cells
are produced daily.
vii. LH production by the pituitary gland regulates the spermatogenesis.
LH binds to Leydig cells receptors and stimulates testosterone
production, which in turn bind to Sertoli cells to promote the
spermatogenesis. FSH binding to the Sertoli cells stimulates
testicular fluid production and synthesis of intracellular androgen
receptor proteins.
viii. Seminal fluid, amounts to about 3 ml and contains 200-300 million
spermatozoa, 30% from the prostate, 60% from seminal vesicles, and

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10% from the epididymis, ampullae, bulbourethral glands and

urethral glands.
ix. Capacitation is a conditioning of the spermatozoon surface that
occurs in the female genital tract, and permits the acrosomal
reaction in the vicinity of the zona pellucida. In the ampulla, sperm
survive and retain their capacity to fertilize an oocyte for 1 - 3 days
(5 days in the laboratory!!!!).
x. Up to 10% spermatozoa may be abnormal without any loss of
fertility, over 20% is infertile. Less than 10 million sperms per ml of
semen are likely to be sterile.
FERTILIZATION
a. Takes place in the lateral third of the uterine tube (ampulla). Spermatozoa
may remain viable in the female reproductive tract for several days. The trip
from cervix to oviduct can occur as rapidly as 30 minutes or as slow as 6
days.
i. After reaching the isthmus, sperm become less motile and cease their
migration. At ovulation, sperm again become motile, perhaps
because of chemoatractants produced by cumulus cells surrounding
the egg.
b. Spermatozoa must undergo (1) capacitation and 2) the acrosome reaction
to acquire fertilization capability.
i. Capacitation is a period of conditioning in the female reproductive
tract, lasts approximately 7 hours. Involves epithelial interactions
between the sperm and the mucosal surface of the tube. A
glycoprotein coat and seminal plasma membrane that overlies the
acrosomal region are removed. Capacitated sperm can pass through
the corona cells and undergo the
ii. Acrosome reaction, occurs after binding to the zona pellucida,
culminates in the release of enzymes needed to penetrate the ZP.
Include acrosin and trypsin-like substances as hyaluronidase penetration of the corona radiata.
c. Phases of fertilization
i. Phase I: penetration of the corona radiate. Only 300-500
spermatozoa reach the site of fertilization.
ii. Phase 2: penetration of the Zona Pellucida Attachment of the
sperm cell to the zona pellucida is mediate by the ZP-3 molecule,
which also stimulates the acrosome reaction of the spermatozoon.
The acrosome reaction involves the fusion of the outer acrosome
membrane with the plasma membrane of the sperm cell and the
fragmentation of the fused membranes. After fusion of the sperm to
the egg membrane a rapid electrical depolarization produces the first
block to polyspermy (fast block) in the egg. This is almost
immediately followed by a wave of calcium ions that causes the
cortical granules to release their contents into the perivitelline
space and ultimately inactivate the sperm receptors in the zona
pellucida (slow block).
iii. Phase 3: fusion of the oocyte and sperm cell membranes.After
entry of the sperm into the egg, the nuclear material of the sperm
decondenses and forms the male pronucleus. At the same time the

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egg completes the second meiotic division and the remaining nuclear
material form the female pronucleus.
d. When the male and female pronuclei join and their chromosomes become
organized for a mitotic division, fertilization is complete, and the fertilized
egg is properly called a zygote.
e. The main results of fertilization are:
i. Restoration of the diploid number of chromosomes.
ii. Determination of the sex of the new individual.
iii. Initiation of cleavage.
III.

CLEAVAGE AND IMPLANTATION

a. Cleavage - a rapid succession of mitotic division, which produces large
numbers of small cells, called blastomeres.
b. After the third cleavage, blastomeres maximize their contact with each other,
forming a compact ball of cells held together by tight junctions. 3 days after
fertilization cells forms a 16-cell morula, enter a stage of compaction.
c. Inner cells of the morula constitute the inner cell mass (gives rise to the
embryo proper) and surrounding cells compose the outer cell mass (forms
the trophoblast which later contributes to the placenta). By 4 days, a fluid
filled blastocoele forms, and becomes a blastocyst, with an inner cell mass
now called the embryoblast, surrounded by a trophoblast.
d. Implantation of the embryo into the uterine lining involves: apposition of
the hatched blastocyst to the endometrial epithelium, penetration of the
uterine epithelium, invasion into the tissues underlying the epithelium, and
erosion of the maternal vascular supply. L selectin on throphoblast cells and
carbohydrate receptors on the uterine epithelium mediate initial attachment
of the blastocyst to the uterus.
e. Further attachment and invasion involve integrins, and the extracellular
matrix molecules laminin and fibronectin. Integrins receptors for laminin
promote attachment, while those for fibronectin stimulate migration.
Implantation is result of mutual trophoblastic and endometrial action.
f. In response to the implanting embryo cells of the endometrium become
polyhedral and loaded with glycogen and lipids, intercellular space are filled
with extravasate and the tissue is edematous, and undergoes the decidual
reaction.
g. In the absence of the implanted embryo, the corpus luteum normally
degenerates after about 13 days. If implantation occurs, the cells of the
trophoblast produce the hormone human chorionic gonadotropin (hCG),
which supports the corpus luteum and thus maintains the supply of
progesterone. Corpus luteum continues to secrete sex steroids for 11 - 12
weeks.
h. Ectopic implantation, implantation into a site other than the upper uterine
cavity. Tubal pregnancy is the most frequent ectopic site. The tube usually
ruptures during the second month of pregnancy, resulting in severe internal
hemorrhaging.
i. Implantation in the uterus itself may lead to serious complication,
particularly if implantation occurs near the internal os (low uterus). The
placenta then bridges the os, is called placenta previa, which results in
severe bleeding in the latter or second part of pregnancy and during delivery.

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CLINICAL CORRELATES:
Review the teal boxes and the problems to solve at the end of each chapter in your
textbook.
Teratoma tumors of disputed origin that often contains a variety of tissues, such as
bone, hair muscle, gut epithelia and others. Some evidence suggests that PGCs
(primordial germ cells) that have strayed from their normal migratory paths could be
responsible for some of these tumors. Epiblast cells may be responsible
Abnormal gametes.
Ovarian follicles occasionally contain two or three primary oocytes. Although these
oocytes may give rise to twins or triplets, they usually degenerate before reaching
maturity.
Abnormal spermatozoa are seen frequently, and up to 10% of all spermatozoa have
observable defects. Sperm with morphological abnormalities lack normal motility and
probably do not fertilize oocytes.
Chromosomal abnormalities (numerical or structural)
50% of conceptions end in spontaneous abortion and 50% of these abortuses have major
chromosomal abnormalities. Thus 25% of conceptuses have a major chromosomal
defect.
45,X (Turner syndrome), triploidy and trisomy 16 are the most common chromosomal
abnormalities in aboruses.
10% of major birth defects are accounted to chromosomal abnormalities. 8% are
accounted to gene mutations.
Numerical abnormalities
Diploid (2n), haploid (n)
Euploid, Aneuploid
Trisomy, Monosomy
Nondisjunction
Mitotic nondisjunction, mosaicism
Translocations (balanced or unbalanced)
Deletion
Microdeletions

Must be reviewed from the textbook.

Trisomy 21 (Down syndrome), extra copy of chromosome 21

Trisomy 18, low-set ears, flexion of fingers and hands, mental retardation,
micrognathia heart and renal anomalies
Trisomy 13, holoprosencephaly cleft lip and palate, anophthalmia and coloboma

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Klinefelter syndrome, XXY, gynecomastia, sterility, testicular atrophy

Turner syndrome, XO (45,X), only monosomy compatible with life, gonadal
dysgenesis, webbed neck. Non-disjunction in the male gamete is the cause.
Triple X syndrome, often go undiagnosed, frequently have problems with speech
and self-esteem
Structural abnormalities
Deletion (partial) of the short arm of chromosome 5, Cri-du-chat syndrome, cat-like
cry, microcephaly.
Microdeletions
Genomic imprinting, characteristics are differentially expressed depending
upon whether the genetic material is inherited from the mother or the father.
a. Angelmans syndrome, microdeletion is in the maternal
chromosome on the long arm of chromosome 15 (15qII-I5q13).
b. Prader-Willi syndrome, microdeletion is in the paternal
chromosome on the long arm of chromosome 15 (15qII-I5q13).
Miller-Dieker syndrome, lissencephaly, developmental delay, seizures, and
cardiac and facial abnormalities resulting from deletion at 17pI3
22qII syndrome, palatal defects, conotruncal heart defects,, speech delay,
learning disorders, and schizophrenia-like disorder resulting from a deletion
in 22qII.
Fragile sites are regions of chromosomes that demonstrate a propensity to
separate or break under certain cell manipulations. Fragile X syndrome, on
the long arm of the X chromosome, Xq27, intellectual disability, large ears,
prominent jaw and large testes. Males are almost exclusively, Fragile X
syndrome is second only to Down syndrome as a cause of intellectual
disability due to genetic abnormalities (1:5,000).
Gene mutations
Single gene mutation, birth defects directly attributable to a change in the
structure or a function of single gene. Account for approximately 8% of all
human malformations.
a. If mutant gene produces an abnormality in a single dose, despite the
presence of a normal allele, it is a dominant mutation.
b. If both alleles must be abnormal (double dose) or if the mutation is Xlinked (occurs on the X chromosome) in the male, it is a recessive
mutation.
c. Inborn errors of metabolism, caused by mutations:
a. Phenylketonuria
b. Homocystinuria
c. Galactosemia

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Mittelschmerz (middledpain), occurs near the middle of the menstrual cycle. Slight pain
felled by some women during ovulation. Basal temperature generally accompanies
ovulation, monitored to help couples in becoming pregnant or preventing pregnancy.
Contraceptive Methods
Barrier methods: male condom, female condom, diaphragm, cervical cap and the
contraceptive sponge.
Hormonal methods: birth control pills, two types: the first is combination of
estrogen and the progesterone analogue progestin; the second is comprised of
progestin alone. This hormones inhibits ovulation, changes the lining of the uterus
and thickening cervical mucus, making it difficult for sperm to enter the uterus.
Male pill, contains synthetic androgen that prevent both LH and FSH secretion and
either stops sperm production to a level of infertility.
Intrauterine device (IUD), two types: hormonal and copper. The hormonal device
releases progestin. The copper device releases copper that prevents fertilization or
implantation. It also prevents sperm from entering the uterine tubes.
Emergency contraceptive pills (ECPs), may prevent pregnancy if taken 120 hours
after sexual intercourse. May be administered as high doses of progestin alone or in
combination with estrogen, EXPs (mifepristone, RU-386) and ulipristal acetate (ella).
Are effective as antihormonal agents or abortifacient.
Sterilization, the method for men is vasectomy. For women is tubal sterilization.
Infertility is a problem for 15% to 30% of couples. Normally the ejaculate has a volume of
2 to 5 mL, 100 million sperm per milliliter or 50 million sperm per total ejaculate are usually
fertile. In women may be due to occluded uterine tubes, hostile cervical mucus, immunity to
spermatozoa, absence of ovulation, and others.
Assisted reproductive technology (ART), one percent of all pregnancies in USA.
Shows increases in prematurity (~37 weeks), low birth weight (~2,500 g); very low
birth weight ( -1,500 g) and higher rate of birth defects.
In vitro fertilization (IVF), Egg is placed in a simple culture medium, and
sperm are added immediately. Fertilized egg are monitored to the eight-cell
stage and then placed in the uterus to develop to term.
Success rate of IVF depends upon maternal age. 30% of couples will
conceive after one attempt if the woman is younger than 35 years of age.
25% for women age 35-37, 17% for those aged 38-40, and to less than 5% of
those over 40. The technique is also associated with higher rate of congenital
malformations. To increase chances of successful pregnancy, four or five
ova are collected, fertilized and placed in the uterus. This approach
sometimes leads to multiple births.
Intracytoplasmic sperm injection, a single sperm is injected into the
cytoplasm of the egg to cause fertilization. This technique carries an
increased risk for fetuses to have Y chromosome deletions but no other

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chromosomal abnormalities. Ejaculate contains very few live sperm

oligozoospermia, no live sperm azoospermia.
Embryonic stem cells, from the inner cell mass of the embryo. Are pluripotent, they
have the potential for curing a variety of diseases.
Adult stem cells, are restricted in their ability to form different cell types and,
therefore are multipotent, not pluripotent. Disadvantages of these cells include slow
rates of cell division and their scarcity.
Abnormal zygotes, 50% of pregnancies end in spontaneous abortion and 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.