PUBERTY | 68

Stages of Life
 PUBERTY | 69

Puberty

Puberty is the stage of development at which individuals become sexually mature. Though the outcomes of
puberty for males and females are very different, the hormonal control of the process is very similar. In addition,
though the timing of these events varies between individuals, the sequence of changes that occur is predictable for
male and female adolescents. Figure 1 shows a concerted release of hormones from the hypothalamus (GnRH),
the anterior pituitary (LH and FSH), and the gonads (either testosterone or estrogen) is responsible for the
maturation of the reproductive systems and the development of secondary sex characteristics, which are
physical changes that serve auxiliary roles in reproduction.

Figure 1. Hormones of Puberty During puberty, the release of LH and FSH from the anterior
pituitary stimulates the gonads to produce sex hormones in both male and female
adolescents.

The first changes begin around the age of eight or nine when the production of LH becomes detectable.
 PUBERTY | 70

The release of LH occurs primarily at night during sleep and precedes the physical changes of puberty by several
years. In pre-pubertal children, the sensitivity of the negative feedback system in the hypothalamus and pituitary is
very high. In other words, very low concentrations of androgens or estrogens will cause negative feedback onto
the hypothalamus and pituitary, keeping the production of GnRH, LH, and FSH low.

As an individual approaches puberty, two changes in sensitivity occur. The first is a decrease of sensitivity in the
hypothalamus and pituitary to negative feedback, meaning that it takes increasingly larger concentrations of sex
steroid hormones to stop the production of LH and FSH. The second change in sensitivity is an increase in
sensitivity of the gonads to the FSH and LH signals, meaning the gonads of adults are more responsive to
gonadotropins than the gonads of children. As a result of these two changes, the levels of LH and FSH slowly
increase and lead to the enlargement and maturation of the gonads, which in turn leads to the secretion of higher
levels of sex hormones and the initiation of spermatogenesis and folliculogenesis.

In addition to age, multiple factors can affect the age of onset of puberty, including genetics, environment, and
psychological stress. One of the more important influences may be nutrition; historical data demonstrate the effect
of better and more consistent nutrition on the age of menarche in girls in the United States, which decreased from
an average age of approximately 17 years of age in 1860 to the current age of approximately 12.75 years in 1960,
as it remains today. Some studies indicate a link between puberty onset and the amount of stored fat in an
individual. This effect is more pronounced in females but has been documented in both sexes. Body fat,
corresponding with the secretion of the hormone leptin by adipose cells, appears to have a strong role in
determining when menarche occurs. This may reflect, to some extent, the high metabolic costs of gestation and
lactation. In individuals who are lean and highly active, such as gymnasts, there is often a delay in the onset of
puberty.

Signs of Puberty

Different sex steroid hormone concentrations between the sexes also contribute to the development and function
of secondary sexual characteristics.

Female Puberty

As a female reaches puberty, typically the first change that is visible is the development of the breast tissue due to
the unopposed low dose estrogen stimulation for about two years before the first menses. This is followed by the
growth of axillary and pubic hair. A growth spurt normally starts at approximately age 9 to 11, and may last two
years or more. During this time, there is weight gain and an increase in body fat distribution, especially in the hips
and thighs. Height can increase 3 inches a year.
 PUBERTY | 71

Changes in the reproductive organs happen as the vagina lengthens and the labia majora and minora become
thickened and rugated. These are followed by the start of menstruation and the first bleeding, menarche . Usually,
menarche occurs two years after breast bud development due to fluctuating estrogen levels associated with follicle
development. The age of menarche has currently declined to 12.2 years in the United States. Ovulation usually
occurs within six months from the first episode of vaginal bleeding.

Male Puberty

In males, the growth of the testes is typically the first physical sign of the beginning of puberty and begins at a
mean age of 11.6. This is followed by growth and pigmentation of the scrotum and growth of the penis. The adult
size and shape of the penis and scrotum is achieved between ages 12 and 17 with an average of about 15 years
of age. Next, increased hair growth occurs, including in the armpit, pubic, chest, and facial hair. Pubic hair
development is complete at 15 years of age. Testosterone stimulates the growth of the larynx and thickening and
lengthening of the vocal folds, which causes the voice to drop in pitch, at an average age of 13.

Spontaneous erection and nocturnal emission may occur, which decrease gradually. The first fertile ejaculations
typically appear at approximately 15 years of age, but this age can vary widely across individuals. Unlike the early
growth spurt observed in females, the male growth spurt occurs toward the end of puberty, at approximately age
11 to 13. The growth spurt continues over time, with 45% of the adult skeletal mass acquired between age 11 and
age 18. A youth’s height can increase as much as 4 inches a year. In some males, development can continue
through the early 20s.

Table 1.: Examples of secondary sexual characteristics are listed.

Male Female
Deposition of fat, predominantly in breasts and
Increased larynx size and deepening of the voice
hips
Increased muscular development Breast development
Growth of facial, axillary, and pubic hair, and increased Broadening of the pelvis and growth of axillary and
growth of body hair pubic hair

Image Sources

• Figure 1. “Hormones of Puberty” is from OpenStax Anatomy & Physiology 2E, licensed CC BY 4.0. Access for
free at OpenStax Anatomy and Physiology 2E online.
 MENOPAUSE | 72

Menopause

Menopause is a permanent cessation of menses because of a loss of ovarian activity, usually identified
retrospectively when an older female has not had a period for over a year. The age of menopause varies
depending on various inherited and environmental factors. The average age of menopause in American women is
51 (range 48-55 years). If menopause happens before the age of 40, that is considered premature menopause.
Some factors like cigarette smoking, living at high altitudes, exposure to some chemotherapeutic agents, or
hysterectomy tend to slightly lower the age of menopause and cause the final cessation of ovulation leading to
early menopause.

Perimenopause

Perimenopause is the time just before and after menopause, around the age of 45-55 years. This time is
considered a transition to menopause. It is associated with the early onset of symptoms like mood swings,
vasomotor flushes, sleep disturbances, headaches, memory problems, decreased libido, urinary incontinence, and
irregular cycles. It is accompanied by fluctuations in ovarian function, decreased number and maturation of the
remaining follicles, and decreased sensitivity to gonadotropin. Fertility rates are markedly reduced, but conception
can occur, as exhaustion of all follicles is not complete yet.

Hormonal changes at menopause

Figure 1. Hormones during the menstrual cycle and at menopause.

 MENOPAUSE | 73

During the transition from menses to menopause, there are some hormonal changes due to the decrease in
ovarian cells’ sensitivity to gonadotropin stimulation, exhaustion of the supply of ovarian follicles, and loss of
ovarian cells that secrete estrogen and progesterone. As a result, estrogen and inhibin levels are reduced.
Decreased estrogen and inhibin remove the negative feedback on the higher centers. As the negative feedback is
removed, gonadotropin, FSH, and LHs level are increased (Figure 1). A state of hypergonadotropic-amenorrhea
develops among menopausal women.

Effects of Estrogen Deficiency

The deficiency of estrogen can cause many physical complaints and changes in menopausal women, which
include:

Vasomotor Instability

The most common complaint, and approximately 70% of symptoms presented in menopausal women, relate to
vasomotor instability. This includes hot flashes due to inappropriate stimulation of the body’s heat-releasing
mechanisms by the hypothalamus, and can last up to 2 years in women. Vasomotor instability can also cause
vasodilation, redness, palpitations, and tachycardia. Vasomotor instability can be severe at night, during stress, or
when eating hot or spicy foods.

Urogenital Changes

Urogenital changes are marked by vaginal dryness, vaginal irritation, and itching. Loss of vaginal elasticity, size,
vascularization, and decrease in vaginal acidity occur, leading to dyspareunia, or painful intercourse.

The atrophy of external genitalia occurs, the labia majora lose its fat, and the labia minora lose pigmentation and
became pale. Weakness of the pelvic ligaments increases the tendency of uterine prolapse. Atrophy of the urethra
and bladder mucosa occurs, leading to loss of urinary wall elasticity and urinary incontinence. Urogenital atrophy
can cause recurrent genital and urinary tract infections.

Cardiovascular Changes

Estrogen deficiency also increases the incidences of cardiovascular disease. In non-menopausal women, estrogen
can stimulate coronary and cerebral blood flow and affect the lipid profile by increasing the
 MENOPAUSE | 74

HDL/LDL ratio and inhibiting plaque formation. As estrogen decreases in menopause, the HDL/LDL ratio
decreases, and LDL levels rise, increasing the potential for heart attacks and strokes.

Skin Changes

Other physical symptoms of postmenopausal women include an increase in facial hair due to a relative increase in
androgens, atrophy of glandular tissue in the mammary glands and its replacement by fatty tissue, and the loss of
collagen fibers in the dermis, leading to thin, dry skin with dark spots. Low estrogen at menopause could also
decrease cognitive function and lead to mood instability.

Osteoporosis

There is a direct relationship between the lack of estrogen and osteoporosis. An individual experiencing
menopause has a high chance to develop osteoporosis due to decreased estrogen levels. Osteoporosis is
usually accelerated 5 to 7 years after menopause. An activation of osteoclast bone cells is increased, leading to a
decrease in bone density and loss of bone matrix and minerals.

Figure 2. Graph showing relationship between age and bone mass.

Menopausal women have a high tendency to have brittle bones and an increased risk of pathologic bone
fractures and spinal deformities. Kyphosis may be developed. Osteoporosis can be prevented by increasing
calcium and protein intake along with exercise. Estrogen hormones may be recommended in severe cases.
 MENOPAUSE | 75

Estrogen Replacement Therapy (ERT)

To reverse the effects of menopause, some women may be advised to partake in estrogen replacement therapy
(ERT). ERT significantly improves vasomotor instability, night sweats, and hot flashes. It also relieves most
urogenital symptoms, dryness, itching, and pain during sex. However, ERT does not relieve vaginal stenosis. ERT
can also relieve depression, insomnia, and improve mood changes. Estrogen replacement plays a vital role in
inhibiting osteoclast activity, preventing bone resorption and bone loss. Thus, estrogen replacement helps in
reducing the incidence of wrist, hip, and vertebral fractures.

Estrogen replacement also increases the survival rate in menopausal women with a previous coronary stenosis or
heart attack. It lowers blood cholesterol and increases coronary blood flow, causing a 50% reduction in
cardiovascular danger and reducing the risk of stroke.

Estrogen Replacement and Cancer Development

Correlating estrogen intake and cancer development is controversial. While estrogen replacement can reduce the
risk of colon cancer, an over-intake of estrogen stimulates endometrial cell proliferation, leading to endometrial
hypoplasia and endometrial cancer. Studies have also shown that the prolonged intake of estrogen more than 10
years could increase the risk for breast cancer development.

Andropause

Menopause in men starts with the decrease in androgen, called andropause. Andropause does not occur as an
abrupt and noticeable event like in women, but it occurs gradually. Androgen (Testosterone) levels begin to decline
gradually around the age of 40, about 1% per year. That decline is not enough to account for any decrease in
libido or erectile function. However, as testosterone level continues to decline with advanced age, facial hair
growth may decrease, the penis and scrotum may shrink, a slight decrease in libido may occur, and erections may
take a longer time to achieve.

Male aging may also be accompanied by some changes in adrenal function. Adrenal glands androgenic hormones
may continue decreasing, leading to decreased vigor and muscular flexibility, and a decline in muscle mass and
strength. The chance of osteoporosis in men also increases.

Research has suggested that the administration of the steroid DHEAS in middle-aged men can increase lean body
mass. However, that may lead to a potential enlargement of the prostate, increase of testicular shrinkage, and
limited sperm production. Its administration should be taken under extreme supervision.
 MENOPAUSE | 76

Image Sources

• Figure 1. “Hormones during the menstrual cycle” was developed for this volume and available under
the same license.
• Figure 2. “Graph showing relationship between age and bone mass” is taken from OpenStax Anatomy &
Physiology, licensed CC BY 4.0. Access for free at https://openstax.org/books/anatomy- and-physiology/.
 | 77

Gametogenesis, Fertilization, and Implantation

 | 78

Gametogenesis

Mitosis and meiosis are the two important cell cycles that aid in the growth and development of the human body
and reproduction. Mitosis aids in the growth and replacement of old cells, a process called cytogenesis. Mitosis is
a type of asexual reproduction, wherein a single parent diploid cell undergoes division, yielding two diploid
daughter cells that are genetically identical to the parent cell.

In contrast, meiosis is a crucial mechanism for generating new cells through sexual reproduction. Meiosis involves
two distinct stages, meiosis I and meiosis II, which are essential during gametogenesis to produce four unique
haploid daughter cells.

In both cycles, DNA replication occurs first, where the nuclear membrane breaks down and the organism’s DNA
condenses to form chromosomes. A key difference between mitosis and meiosis is that during meiosis, when the
chromosomes come together, they “cross over,” which allows for the exchange and “mixing” of the DNA coding.
After that, the chromosomes separate and migrate to the opposite ends of the cell. Upon the completion of meiosis
I and II, the cell divides into 4 distinct, haploid daughter cells, each with its own characteristics.

Gametogenesis is the process of producing gametes, specialized reproductive cells. This process occurs through
the cell cycle of meiosis and produces cells with a haploid number of chromosomes. The process of producing
gametes in males is called spermatogenesis, and in females, it is called oogenesis. Spermatogenesis leads to
the formation of sperm, while oogenesis results in the development of eggs (ova). These processes occur in the
testes for males and the ovaries for females, respectively, and are essential for sexual reproduction.

Spermatogenesis

Spermatogenesis occurs in the seminiferous tubules that form the bulk of each testis. The process begins at
puberty, after which time sperm are produced constantly throughout the lifespan. One production cycle, from
spermatogonia to formed sperm, takes approximately 64 days. A new cycle starts approximately every 16 days,
although this timing is not synchronous across the seminiferous tubules. The total number of sperms a man
produces slowly declines after age 35, and some studies suggest that smoking can lower sperm counts
irrespective of age.

The process of spermatogenesis begins with mitosis of the diploid spermatogonia. Because these cells are diploid
(2n), they each have a complete copy of the father’s genetic material, 46 chromosomes.
 GAMETOGENESIS | 79

However, mature gametes are haploid (1n), containing 23 chromosomes—meaning that daughter cells of
spermatogonia must undergo a second cellular division through the process of meiosis.

Figure 1. Spermatogenesis (a) Mitosis of a spermatogonial stem cell involves a single cell division that results in two identical,
diploid daughter cells (spermatogonia to primary spermatocyte). Meiosis has two rounds of cell division: primary
spermatocyte to secondary spermatocyte, and then secondary spermatocyte to spermatid. This produces four haploid
daughter cells (spermatids). (b) In this electron micrograph of a cross-section of a seminiferous tubule from a rat, the lumen is
the light-shaded area in the center of the image. The location of the primary spermatocytes is near the basement membrane,
and the early spermatids are approaching the lumen (tissue source: rat). EM × 900.

The cycle starts at puberty, where the spermatogonium cell goes through mitosis. Two identical diploid cells result
from spermatogonia mitosis. One of these cells remains a spermatogonium, and the other becomes a primary
spermatocyte. The next stage is the process of spermatogenesis. As in mitosis, DNA is replicated in a primary
spermatocyte before it undergoes a cell division called meiosis I. During meiosis I, each of the 23 pairs of
chromosomes separates. This results in two cells, called secondary spermatocytes, each with only half the number
of chromosomes. Then, a second round of cell division (meiosis II) occurs in both secondary spermatocytes.
During meiosis II, each of the 23 replicated
 GAMETOGENESIS | 80

chromosomes divides, similar to what happens during mitosis. Thus, meiosis results in separating the
chromosome pairs. This second meiotic division results in four cells with only half the number of chromosomes.
Each of these new cells is a spermatid. Although haploid, early spermatids look very similar to cells in the earlier
stages of spermatogenesis, with a round shape, central nucleus, and a large amount of cytoplasm. A process
called spermiogenesis transforms these early spermatids, reducing the cytoplasm and beginning the formation
of the parts of a true sperm. The fifth stage of germ cell formation—spermatozoa or formed sperm—is the end
result of this process, which occurs in the portion of the tubule nearest the lumen. Eventually, the sperm are
released into the lumen and are moved along a series of ducts in the testis toward a structure called the
epididymis for the next step of sperm maturation.

Oogenesis

Oogenesis process begins with the ovarian stem cells, or oogonia. Oogonia are formed during fetal development
and divide via mitosis, much like spermatogonia in the testis. Unlike spermatogonia, however, oogonia forms
primary oocytes in the fetal ovary prior to birth. These primary oocytes are then arrested in this stage of meiosis I,
only to resume it years later, beginning at puberty and continuing until the woman is near menopause (the
cessation of a woman’s reproductive functions). The number of primary oocytes present in the ovaries declines
from one to two million in an infant, to approximately 400,000 at puberty, to zero by the end of menopause.

The initiation of ovulation—the release of an oocyte from the ovary—marks the transition from puberty into
reproductive maturity in females. From then on, throughout the reproductive years, ovulation occurs approximately
once every 28 days. Just prior to ovulation, a surge of luteinizing hormone triggers the resumption of meiosis in a
primary oocyte. This initiates the transition from primary to secondary oocyte. However, as shown in the figure
below, this cell division does not result in two identical cells. Instead, the cytoplasm is divided unequally, and one
daughter cell is much larger than the other. This larger cell, the secondary oocyte, eventually leaves the ovary
during ovulation. The smaller cell, called the first polar body, may or may not complete meiosis and produce
second polar bodies; in either case, it eventually disintegrates. Therefore, although oogenesis produces up to four
cells, only one survives.
 GAMETOGENESIS | 81

Figure 2. Oogenesis The unequal cell division of oogenesis produces one to three polar bodies that later degrade, as well as
a single haploid ovum, which is produced only if there is penetration of the secondary oocyte by a sperm cell.

How does the diploid secondary oocyte become an ovum—the haploid female gamete? Meiosis of a secondary
oocyte is completed only if a sperm succeeds in penetrating its barriers. Meiosis II then resumes, producing one
haploid ovum that, after fertilization by a (haploid) sperm, becomes the first diploid cell of the new offspring (a
zygote). Thus, the ovum can be considered a brief, transitional, haploid stage between the diploid oocyte and
diploid zygote.

The larger amount of cytoplasm contained in the female gamete is used to supply the developing zygote with
nutrients between fertilization and implantation into the uterus. Interestingly, sperm contribute only DNA at
fertilization—not cytoplasm. Therefore, the cytoplasm and all of the cytoplasmic organelles
 GAMETOGENESIS | 82

in the developing embryo are of maternal origin. This includes mitochondria, which contain their own DNA.
Scientific research in the 1980s determined that mitochondrial DNA was maternally inherited, meaning that you
can trace your mitochondrial DNA directly to your mother, her mother, and so on back through your female
ancestors.

Take Home Message

• Spermatogenesis starts at puberty while oogenesis starts before birth.
• A spermatid is a large cell that loses its cytoplasm and eventually becomes sperm.
• Primary oocytes enter meiosis and stop at the prophase stage of meiosis I. They complete meiosis I
at ovulation.
• An LH peak is required for secondary oocyte development.
• Fertilization stimulates the completion of meiosis II and ova development.

Image Sources

• Figure 1. “Spermatogenesis” is from OpenStax Anatomy & Physiology 2E, CC BY 4.0. Access for free at
OpenStax Anatomy and Physiology 2E online. Micrograph image provided by the Regents of University of
Michigan Medical School © 2012.
• Figure 2. “Oogenesis” is from OpenStax Anatomy & Physiology 2E, CC BY 4.0. Access for free at
OpenStax Anatomy and Physiology 2E online.
 FERTILIZATION | 83

Fertilization

Fertilization is the process by which gametes (an egg and sperm) fuse to form a zygote. Through it, a number of
steps and reactions occur. During ejaculation, hundreds of millions of sperm (spermatozoa) are released into the
vagina. Almost immediately, millions of these sperm are overcome by the acidity of the vagina (approximately pH
3.8), and millions more may be blocked from entering the uterus by thick cervical mucus. Of those that do enter,
thousands are destroyed by phagocytic uterine leukocytes. The race into the uterine tubes, the most typical site for
sperm to encounter the oocyte, is reduced to a few thousand contenders. The sperms must make their way into
one of the two uterine tubes (fallopian tubes) to meet the egg, and overcome the cilia that work only in the direction
of the uterine cavity. Approximately 100–1000 sperms reach the ampulla, the site of fertilization, where about 20–
200 sperms meet the oocyte cell mass.

The journey through the female reproductive system to reach the oocyte is thought to be facilitated by uterine
contractions which usually take around 30 minutes to 2 hours. A healthy sperm could reach the ampulla within 30
minutes. If the sperm do not encounter an oocyte immediately, they can survive in the uterine tubes for another
48–72 hours. Thus, fertilization can still occur if intercourse takes place a few days before ovulation. In
comparison, an oocyte can survive independently for only approximately 24 hours following ovulation. Therefore,
intercourse more than a day after ovulation will usually not result in fertilization.

During the journey, fluids in the female reproductive tract prepare the sperm for fertilization through a process
called capacitation, or priming. The fluids improve the motility of the spermatozoa. They also deplete cholesterol
molecules embedded in the membrane of the head of the sperm, thinning the membrane in such a way that will
help facilitate the release of the lysosomal (digestive) enzymes needed for the sperm to penetrate the oocyte’s
exterior once contact is made. Sperm must undergo the process of capacitation to have the “capacity” to fertilize
an oocyte. If they reach the oocyte before capacitation is complete, they will be unable to penetrate the oocyte’s
thick outer layer of cells.

Contact Between Sperm and Oocyte

Upon ovulation, the oocyte released by the ovary is swept into—and along—the uterine tube. Fertilization must
occur in the distal uterine tube because an unfertilized oocyte cannot survive the 72-hour journey to the
uterus. The released oocyte is a secondary oocyte surrounded by two protective layers. The corona radiata is an
outer layer of follicular (granulosa) cells that form around a developing oocyte in the ovary and remain with it
upon ovulation. The underlying zona pellucida (pellucid =
 FERTILIZATION | 84

“transparent”) is a transparent, but thick, glycoprotein membrane that surrounds the cell’s plasma membrane.

As the oocyte is swept along the distal uterine tube, the oocyte encounters the surviving capacitated sperm, which
stream toward it in response to chemical attractants released by the cells of the corona radiata. To reach the
oocyte itself, the sperm must penetrate the two protective layers. The sperm first burrow through the cells of the
corona radiata. Then, upon contact with the zona pellucida, the sperm bind to receptors in the zona pellucida. This
initiates a process called the acrosomal reaction, in which the enzyme-filled “cap” of the sperm, called the
acrosome, releases its stored digestive enzymes. These enzymes clear a path through the zona pellucida,
allowing sperm to reach the oocyte. Finally, a single sperm makes contact with sperm-binding receptors on the
oocyte’s plasma membrane. The plasma membrane of the sperm then fuses with the oocyte’s plasma membrane,
and the head and mid-piece of the “winning” sperm enter the oocyte interior.

Figure 1. The fertilization process (Image Source: OpenStax Anatomy & Physiology 2E, CC BY 4.0. Access for free at OpenStax
Anatomy and Physiology 2E online)

How do sperm penetrate the corona radiata? Some sperm undergo a spontaneous acrosomal reaction,
 FERTILIZATION | 85

an acrosomal reaction that is not triggered by contact with the zona pellucida. The digestive enzymes released by
this reaction digest the extracellular matrix of the corona radiata. As you can see, the first sperm to reach the
oocyte is never the one to fertilize it. Rather, hundreds of sperm cells must undergo the acrosomal reaction, each
helping to degrade the corona radiata and zona pellucida until a path is created to allow one sperm to contact and
fuse with the oocyte’s plasma membrane.

Consider the loss of millions of sperm between entry into the vagina and degradation of the zona pellucida.
Taking this into account, you can understand why a low sperm count can cause male infertility.

When the first sperm fuses with the oocyte, the oocyte deploys two mechanisms to prevent polyspermy, or
penetration by more than one sperm. Preventing polyspermy is critical because if more than one sperm were to
fertilize the oocyte, the resulting zygote would be a triploid organism with three sets of chromosomes, and
incompatible with life.

The first mechanism is the fast block, which involves a near-instantaneous change in sodium ion permeability
upon the binding of the first sperm, depolarizing the oocyte plasma membrane and preventing the fusion of
additional sperm cells. The fast block sets in almost immediately and lasts for about a minute.

At the same time, an influx of calcium ions following sperm penetration triggers the second mechanism, the slow
block. In this process, referred to as the cortical reaction, cortical granules sitting immediately below the oocyte
plasma membrane fuse with the membrane and release zonal inhibiting proteins and mucopolysaccharides
into the space between the plasma membrane and the zona pellucida. Zonal inhibiting proteins cause the release
of any other attached sperm and destroy the oocyte’s sperm receptors, thus preventing any more sperm from
binding. The mucopolysaccharides then coat the nascent zygote in an impenetrable barrier that, together with the
hardened zona pellucida, is called a fertilization membrane, or eggshell.

Recall that at the point of fertilization, the oocyte has not yet completed meiosis; all secondary oocytes remain
arrested in metaphase of meiosis II until fertilization. Only upon fertilization does the oocyte complete meiosis. The
unneeded complement of genetic material that results is stored in a second polar body that is eventually ejected.
At this moment, the oocyte has become an ovum, the female haploid gamete. The two haploid nuclei derived from
the sperm and oocyte and contained within the egg are referred to as pronuclei. They decompress, expand, and
replicate their DNA in preparation for mitosis. The pronuclei then migrate toward each other, their nuclear
envelopes disintegrate, and the male- and female-derived genetic material intermingles. This step completes the
process of fertilization and results in a single-celled diploid zygote with all the genetic instructions it needs to
develop into a human. Sex, hair and eye color determination happen at this point.
 FERTILIZATION | 86

Clinical Correlation

Fraternal Twins

Fraternal twins, also known as dizygotic twins, are a type of twins that result from the simultaneous release and
fertilization of two different eggs (oocytes) by two different sperm cells. Fraternal twins are essentially like any
other siblings, with the key difference being that they share the same womb during pregnancy.

Because they develop from separate fertilized eggs, they have their own unique genetic makeup and can be of the
same gender (two brothers or two sisters) or of different genders (a brother and a sister). They share
approximately 50% of their genes, like any other siblings born at different times.

Early Pregnancy Factor

Early pregnancy factor (EPF) is a protein that has been used to describe a substance in the mother’s blood that
seems to be present within hours after conception (fertilization), before the embryo even reached the uterus. This
factor might be involved in preventing the mother’s immune system from rejecting the developing embryo. Ongoing
research is attempting to identify and characterize the specific molecules or factors involved in early pregnancy,
although a universally accepted explanation has yet to be established.

Take Home Message

• An acrosomal reaction is necessary for sperm to penetrate an oocyte.
• Once fertilization occurs, a hardening of the eggshell occurs, preventing polyspermy.
• The fusion of the ovum and sperm’s pronucleus leads to zygote development.
• Early pregnancy factor (EPF) may be used as an indication that fertilization has occurred.

Image Sources

• Figure 1. “The fertilization process” is from OpenStax Anatomy & Physiology 2E, licensed CC BY
4.0. Access for free at OpenStax Anatomy and Physiology 2E online.
 POST FERTILIZATION AND PRE-EMBRYONIC STAGE | 87

Post Fertilization and Pre-Embryonic Stage

Cleavage and Blastocyst Development

Following fertilization, the zygote and its associated membranes, together referred to as the conceptus, continue
to be projected toward the uterus by peristalsis and beating cilia. During its journey to the uterus, the zygote
undergoes five or six rapid mitotic cell divisions. The rapid, multiple rounds of cell division are termed cleavage.
Although each cleavage results in more cells, it does not increase the total volume of the conceptus. Each
daughter cell produced by cleavage is called a blastomere.

Approximately 72 hours after fertilization, a 16-cell conceptus reaches the uterus. The cells that had been loosely
grouped are now compacted and look more like a solid mass. The name given to this structure is the morula.

Figure 1. The figure shows cleavage and early division.

 POST FERTILIZATION AND PRE-EMBRYONIC STAGE | 88

Once inside the uterus, the conceptus floats freely for several more days. It continues to divide, creating a ball of
approximately 100 cells and consuming nutritive endometrial secretions called uterine milk while the uterine lining
thickens. The ball of the tightly bound cells starts to secrete fluid and form a central fluid-filled cavity. At this
developmental stage, approximately 5 days after ovulation, the conceptus is referred to as a blastocyst.

Within the blastocyst, the cells arrange themselves into two layers. A group of cells forms into an inner cell mass
which is fated to become the embryo. The cells that form the outer shell, called trophoblasts, will develop into the
placenta (the organ of nutrient, waste, and gas exchange between mother and the developing embryo).

As the blastocyst forms, the trophoblast excretes enzymes that begin to degrade the zona pellucida. In a
process called “hatching,” the conceptus breaks free of the zona pellucida in preparation for implantation.

Clinical Correlation

Embryonic Stem Cell Research

Up to the 8-cell stage of cleavage, the cells of the conceptus are pluripotent cells, where each cell has the potential
to differentiate into any cell type in the human body, and each can be independently developed into an identical
conceptus. These cells are called embryonic stem cells (ESC) and are widely used in scientific research to better
understand early human development, study diseases, and develop potential treatments. ESCs provide a valuable
model for studying cell differentiation and developmental processes; however, research involving ESCs has been a
topic of ethical debate because their extraction usually involves the destruction of human embryos.

Identical Twins

Identical twins are the result of a single fertilized egg (oocyte) splitting into two embryos. This splitting typically
occurs shortly after fertilization, but it can happen at various stages of development, including before the 16-cell
stage.

When the single fertilized egg splits into two embryos, these twins share the same genetic material, making them
genetically identical. Because they come from the same fertilized egg, they are of the same sex and usually share
a strong resemblance in terms of physical appearance. Identical twins are sometimes called “monozygotic twins”
to highlight their single-egg origin.
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Take Home Message

• The process by which the cells go into mitotic division after fertilization is known as cleavage.
• The solid mass at 16-cell conceptus is called morula.
• The blastocyst is the fluid-filled space within the conceptus developed approximately 5 days
after ovulation.

Image Sources

• Figure 1. “Fetal development first week of pregnancy ” by udaix was licensed through Adobe Stock for
educational use.
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Implantation

Implantation occurs when the conceptus adheres to the wall of the uterus, signaling the end of the pre- embryonic
stage of development.

As the zona pellucida begins to fragment, the blastocyst is able to attach to the uterine endometrium. By this time,
progesterone and estrogen produced by the corpus luteum lead to the proper proliferation and differentiation of the
endometrium. As the endometrium continues its maturation, a decidua layer is formed. The maturation of the
endometrium and formation of a secretory endometrium is called decidualization. Around the end of the first
week, the blastocyst comes into contact with the secretory uterine wall and adheres to it, embedding itself in the
uterine lining via the trophoblast cells. Thus begins the process of implantation.

Figure 1. The graphic shows the trophoblastic tissue, inner cytotrophoblast and outer
syncytiotrophoblast.

The inner cell layer of the trophoblast of the blastocyst, called the cytotrophoblast, forms the fetal surface of the
placenta. The outer layer of the trophoblast, known as the syncytiotrophoblast,
 IMPLANTATION | 91

contributes to the maternal surface of placenta that fuses with endometrial cells. The syncytiotrophoblast cells lose
their cell walls and become the working interface of the placenta. The cytoplasm of the cells fuse and form a
multinucleated cytoplasm. Then, the syncytiotrophoblast layer invaginates into the decidua and is surrounded by
lakes of maternal blood, allowing the efficient transfer of oxygen, nutrients, and waste products bidirectionally
without the direct mixing of maternal and fetal blood.

The syncytiotrophoblast cells produce human chorionic gonadotropin (hCG), a hormone that directs the corpus
luteum to survive, enlarge, and continue producing progesterone and estrogen to suppress menses. These
functions of hCG are necessary for creating an environment suitable for the developing embryo. As a result of this
increased production, hCG accumulates in the maternal bloodstream and is excreted in the urine. Implantation is
complete by the middle of the second week. Just a few days after implantation, the trophoblast has secreted
enough hCG for an at-home urine pregnancy test to give a positive result. hCG is the marker used for mass
pregnancy tests.

Implantation can be accompanied by minor bleeding. The blastocyst typically implants in the fundus of the uterus
or on the posterior wall. However, if the endometrium is not fully developed and is not ready to receive the
blastocyst, the blastocyst will detach and find a better spot. A significant percentage (50–75 percent) of blastocysts
fail to implant; when this occurs, the blastocyst is shed with the endometrium during menses. The high rate of
implantation failure is one reason why pregnancy typically requires several ovulation cycles to achieve.

Clinical Correlation

Precise timing of endometrial lining and implantation

The time from ovulation to implantation takes approximately 10–12 days. Proper timing for the arrival of the
conceptus into the uterine cavity is essential for implantation. During IVF techniques, the maturation of the
endometrium must be coordinated precisely with the developmental stage of the conceptus transferred into the
uterus for optimal pregnancy rates. Attempts at tubal re-anastomosis may be followed by too short of the
oviduct (<4cm). Short tubes might accelerate the transport of the conceptus through the tubes and diminish
pregnancy rates.
 IMPLANTATION | 92

Take Home Message

• Trophoblast cells produce hCG, the marker ised for mass pregnancy tests.
• A positive pregnancy test is an indication that implantation has occurred.

Image Sources

• Figure 1. “Blastocyst implantation” by sakurra was licensed through Adobe Stock for educational use.
 PLACENTA DEVELOPMENT | 93

Placenta Development

The placenta is a vital organ for fetal development. It arises from the trophoblastic layer of the blastocyst. At 14
days after fertilization, the cytotrophoblast, the trophoblast layer facing the fetal side, develops the chorion layer
that wraps around the baby. The outer layer of the trophoblast, the syncytiotrophoblast, forms on the maternal side
of the placenta.

The placenta gradually takes over the corpus luteum’s duties in the secretion of estrogen and progesterone. By the
end of the first trimester, the placenta becomes the primary source of estrogen and progesterone and is
responsible for the continuation of pregnancy, taking over the role of feeding the embryo.

The placenta usually connects to the conceptus via the umbilical cord, which contains the umbilical vessels. The
spaces within the cord and around the blood vessels are filled with Wharton’s jelly, a mucous connective tissue.
The umbilical cord and vessels aid in the transfer of oxygen, nutrients, and waste products without mixing maternal
and fetal blood. Deoxygenated blood and waste leaves the fetus through two umbilical arteries, while nutrients and
oxygen are carried from the mother to the fetus through a single umbilical vein. The umbilical cord is surrounded
by the amnion. The placenta’s initial development as an organ is complete by weeks 14–16 after fertilization.

The placenta grows like an expanding disk. By week 20, the placenta covers half of the uterine wall and weighs
about 200g. At term, it is about 700g and 20cm in diameter. The placenta is highly vascular and if the baby dies or
is delivered, the placenta can keep growing.

Because blood cells cannot move across the placenta, the maternal and fetal blood do not co-mingle. This
separation prevents the mother’s cytotoxic T cells from reaching and subsequently destroying the fetus, which
bears “non-self” antigens. Further, it ensures the fetal red blood cells do not enter the mother’s circulation and
trigger antibody development (if they carry “non-self” antigens) until the final stages of pregnancy or birth. This
separation is why, even in the absence of preventive treatment, an Rh− mother doesn’t develop antibodies that
could cause hemolytic disease in her first Rh+ fetus.

Although blood cells are not exchanged, the placenta is permeable to lipid-soluble fetotoxic substances: alcohol,
nicotine, barbiturates, antibiotics, certain pathogens, and many other substances that can be dangerous or fatal to
the developing embryo or fetus. For these reasons, pregnant women should avoid fetotoxic substances.

The placenta is normally attached and situated in the upper one-third of the anterior or posterior uterine wall
within the endometrium. This placement is conducive to the growth and development of the embryo.
 PLACENTA DEVELOPMENT | 94

Clinical Correlation: Abnormal Attachment of the Placenta

Placenta Previa

Implantation of the placenta occurs in the lower part of the uterus. A place can result in the partial or
complete coverage of the cervical os. As the highly vascularized nature of the placenta, bleeding may occur with
the growing uterus, and early or partial separation of the placenta may happen, and continuation of pregnancy will
be jeopardy.

Figure 1. An embryo that implants too close to the opening of the cervix can lead to
placenta previa, a condition in which the placenta partially or completely covers the cervix.

Placenta Accreta

A condition characterized by placenta attachment directly into the myometrium, placenta accreta is often caused
by defective decidual endometrial layers, uterine inflammation, or old scar tissue from previous cesarean or uterine
surgery. Tied placental implantation in the myometrium will impair placental separation after birth, resulting in
massive bleeding and hemorrhage that may even lead to the death of the mother.
 PLACENTA DEVELOPMENT | 95

Figure 2. Accreta, Increta, and Percreta placenta growth.

Take Home Message

• The placenta is a necessary organ for fetal growth.
• The placenta’s growth is independent of fetal growth.
• Attachment of placenta is typically in the upper 1/3 of the endometrium.

Image Sources

• Figure 1. “Placenta Previa” is from OpenStax Anatomy & Physiology 2E, licensed CC BY 4.0.
 PLACENTA DEVELOPMENT | 96

Access for free at OpenStax Anatomy and Physiology 2E online.

• Figure 2. “Accreta, Increta, and Percreta placenta growth” is adapted by Abbey Elder from “Placenta
Previa” in OpenStax Anatomy & Physiology 2E, licensed CC BY 4.0. Access for free at OpenStax Anatomy
and Physiology 2E online.
 EMBRYOGENESIS | 97

Embryogenesis

Embryogenesis is a very complex system with a slim chance of achieving infant life. Statistical analysis shows
that out of 100 oocytes in the presence of sperm, “84 are fertilized, 69 are implanted, a week later 42 are still alive,
37 survive to the sixth week or pregnancy, and only 31 survive to birth.” 1 In over half of these instances, the cause
for zygote death and miscarriage are due to chromosomal abnormalities. Furthermore, many complex cellular
steps conducted during pregnancy have to be carried out perfectly to ensure a healthy infant.

After implantation, the inner cell mass of the blastocyst that will become the embryo differentiates into two layers:
the epiblast and the hypoblast. The epiblast then gastrulates into three germ layers: the ectoderm, mesoderm,
and endoderm, and develops the embryo. At the same time, the hypoblast will form the extra-embryonic
membranes: the yolk sac, amnion, and allantois.

Throughout fetal growth, many terms correlate to the cell division and the formation of the epiblast. Following the
initial two weeks of development, the term “pre-embryo” is used to refer to the developing structure. From three to
eight weeks post-fertilization, the pre-embryonic cells become distinct and become the “embryo”. Subsequently,
from eight weeks post-fertilization until birth, the developing organism is referred to as the “fetus.”

During early development, cells in the embryo go through a process of differentiation, which involves becoming
specialized to perform specific functions. The position of a given cell relative to others can play a crucial role in
determining its fate or the specific genes it will express. This concept is known as spatial patterning, or
positional information, and implies that the location of a cell within the developing embryo influences the genes it
activates and the type of cell it will become.

In addition to the differentiation of various cell types, many essential structures and organs form to support the
growing embryo and fetus, including the placenta, umbilical cord and amniotic fluid. As the embryo develops
into a fetus, these supportive structures become increasingly important for the well-being of the growing fetus.
They play critical roles in ensuring that the fetus receives the necessary nutrients, oxygen, and protection for
healthy development. The placenta, umbilical cord, and amniotic fluid are intricately linked in their functions,
forming a nurturing environment for the fetus throughout pregnancy.

1. Grobstein, Clifford. “External Human Fertilization.” Scientific American, vol. 240, no. 6, 1979, pp. 57–67.
 EMBRYOGENESIS | 98

Morphogenesis

Morphogenesis refers to the shaping and structuring of an organism’s form. It encompasses a series of
intricate processes responsible for the emergence of the body’s diverse systems and organs. This developmental
journey is a continuous maturation, with all systems and organs initiating their formation in the early stages of
pregnancy, primarily within the first eight weeks of gestation, and their progression continues throughout the
gestational period. This gradual maturation prepares the fetus for its eventual transition to life outside the womb.
Three critical organs that undergo development and determine the potential for fetal survival and health are the
heart, lungs, and nervous system. Their maturation and functions are discussed below.

The cardiovascular system, including the heart, is one of the earliest functional systems to develop, with the
sound of the heartbeat becoming audible as early as five weeks through vaginal probe or by normal stethoscope at
week twelve.

Lung maturity is a critical aspect of fetal development and occurs toward the end of pregnancy, with the proper
production of surfactant, a substance produced by special cells in developing fetal lungs. Surfactant plays a
crucial role in reducing surface tension in the alveoli (tiny air sacs in the lungs). The maturation of the lungs refers
to the readiness of a fetus’s lungs to function effectively in supporting respiration once the infant is born.

The formation of the nervous system, including the central nervous system (CNS) and peripheral nervous
system (PNS), begins very early in embryonic development. The neural tube, which eventually becomes the brain
and spinal cord, forms as others during the first eight weeks after conception. Fat deposition and myelin formation
occur later in fetal development, typically in the third trimester. Myelin is a fatty substance that surrounds nerve
fibers and plays a crucial role in the rapid transmission of nerve impulses. This process continues throughout
pregnancy and even after birth.

Clinical Correlation

Preterm or Premature Infants

Infants who are born before they have reached full term are at higher risk for various complications because some
of their organs and systems may not have fully matured. For example, the risk of respiratory distress in premature
infants is a significant concern because the lungs typically require the last few weeks of pregnancy to develop fully
and become fully functional at birth.

Medical professionals closely monitor lung maturity, especially when managing pregnancies that might
 EMBRYOGENESIS | 99

be at risk for preterm birth. When necessary, interventions may be taken to support lung development, including
the administration of corticosteroids to stimulate surfactant production in the lungs and improve lung maturity.

Developmental Milestones

Uncontrolled urination or defecation in a newborn, often referred to as “involuntary voiding” or “involuntary bowel
movements,” is indeed a common occurrence. This is primarily due to the immaturity of the nervous system and
the myelin sheath at birth.

As the nervous system and myelin sheath continue to mature after birth, infants gradually gain control over these
functions. By the age of 2 or 3, most children have developed the ability to voluntarily control urination and bowel
movements and have achieved toilet training milestones.

Reproductive System Development

The reproductive system is one of the few systems that matures differently based on the sex of embryos. Sex
determination is completed at fertilization. It is well known that females have two X chromosomes, while males
have one X and one Y. Since all eggs carry X chromosomes, the determination of sex is reliant on the sperm’s
contribution. If the sperm has the Y chromosome, the SRY gene is activated, which initiates the expression of the
Testis-Determining Factor (TDF) and leads to the development of the testes. Nevertheless, it is important to note
that it takes time for the gonads to differentiate into their final form.

Internal and External Genitalia Differentiation

At week five of development, a paired bulge is present near the midline at the back of the abdominal cavity. These
are the genital ridges and are indifferent in males and females. Germ cells from the yolk sac will then migrate
toward the genital ridges. Only a week later, indifferent accessory ducts are present. These are the
paramesonephric and mesonephric ducts. It is important to note that external genitalia of the different genders
also arise from the same structures: the genital tubercle, urogenital folds, and labioscrotal swellings.

At week seven, male structures begin to develop. Primordial germ cells that are XY develop the testis, which
secrete testosterone. In males, the paramesonephric ducts degenerate, and the mesonephric ducts develop the
accessory ducts and glands of the reproductive system. Until two months before birth, the testes are located in the
pelvic cavity. Once stimulated by testosterone the testes then descend into the
 EMBRYOGENESIS | 100

scrotum. The scrotum is an external structure developed from labioscrotal swelling due to
testosterone influence. This hormone also causes the genital tubercle to enlarge, forming the penis
and the urogenital fold to form the ventral aspect of the penis.

At week eight, female structures begin to develop. Primordial germ cells that are XX develop the
ovaries that eventually descend into the pelvic cavity to be stopped by the broad ligament at the pelvic
brim. Degeneration of the mesonephric ducts occurs, and the paramesonephric ducts develop into the
oviduct and female genital tract. In the absence of testosterone, the genital tubercle develops into the
clitoris, the urethral groove remains open to develop into the vestibule, the urogenital fold becomes
the labia minora, and the labioscrotal swellings form into the labia majora.