Menstrual cycle, fertilization and implantation

HALE TEKA, M.D,OBGYN
MEKELLE UNIVERSITY
Wednesday, December 4, 2019 HALE TEKA, M.D., OBSTETRICIAN AND GYNECOLOGIST 1
Menstrual Cycle, Fertilization and Implantation

Contents
1. Menstrual Cycle
2. Fertilization
3. Implantation
4. Referrences

Menstrual Cycle: Introduction

Menstrual Cycle
• Tightly coordinated cycle of stimulatory and inhibitory effects that
results in the release of single mature oocyte
 hormones and paracrine and autocrine factors control it

Phases of menstrual cycle
• Menstrual cycle has two phases
Follicular phase
Luteal phase

• Normal menstrual cycle
Cycle: 28 ± 7 days
 Flow: 4 ± 2 days
Volume per cycle: 20 – 60 mL
 No disabling symptoms

• Convention
 By convention first day of vaginal bleeding is considered day -1
of the menstrual cycle

• Menses is most often irregular in
 2 years following menarche
 3 years preceeding menopause

• Early menopausal transition
 shorter interval menses
• Late menopausal transition
 Longer interval menses

• Menstrual cycle is least variable
 Between ages 20 – 40

•The normal human menstrual cycle can be divided into two
segments:
Ovarian cycle
 Uterine cycle

•The ovarian cycle may be further divided into
Preovulatory  Follicular
oRelatively variable
o Reason why women have different cycle lengths
Postovulatory Luteal phase
o Relatively stable, lasting 13 – 14 days

•Uterine cycle is divided into corresponding
Proliferative and
Secretory phases

The Ovarian Cycle

Early Follicular Phase
• The least hormonally active phase
 Low serum estradiol and progesterone concentrations
 Anterior pituitary and hypothalamus released of the negative
feedback effects of estradiol, progesterone and luteal phase inhibin A
o This leads to increase in serum FSH concentration by 30%
 Important for recrutitment of the next cohort of developing follicles

 Serum inhibin B concentrations secreted by the recruitable pool
of small follicles are maximal
o Play a role in suppressing the FSH rise at this time in the cycle
 Rapid increase in LH pulse frequency at this time
oOne pulse every 4 hours in the late luteal phase to one pulse
every 90 minutes in the early follicular phase

• Unique neuroendocrine phenomenon
 Slowing or cessation of LH pulses during sleep that does not
occur at other times of the menstrual cycle

 Serum antimullerian homrone (AMH)
o Minimal variability across the menstrual cycle
o Secreted by small antral follicles and correlated with total
number of ovarian antral follicles

 Ovary is quiescent in the early follicular phase
o occasionally visible resolving corpus luteum from the previous
cycle
o endometrium relatively indistinct during menses and then
becomes a thin line once menses is complete
o It is normal to see small follicles of 3 to 8 mmm in diamter at this
time

Mid-follicular phase
• FSH
 Stimulates folliculogenesis
o Several follicles grow into antral stage
o Granulosa cells hypertrophy and divide
 increased productions of estradiol and inhibin A

 Increased estradiol production
o Feeds back negatively on the hypothalamus and pituitary
 Mean serum FSH and LH concentrations suppressed
 Suppressed LH pulse amplitude

Late Follicular Phase
• Estradiol and inhibin A
 increase daily during the week before ovulation due to release
from the growing follicle
• FSH and LH concentrations
Fall at this time due to negative feedback effects of estradiol
and perhaps other hormones released from the ovary

 Single dominant follicle selected
 Dominant follicle increase in size by approximately 2 mm per
day until a mature size of 20 – 26 mm is reached

Luteal Phase: Mid – cylce surge and ovulation
• Serum estradiol concentations continue to rise untill they reach a
peak approximately one day before ovulation
• Sudden 10 fold increase in serum LH concentations and a smaller
rise in serum FSH concentations
 For poorly understood reasons

• Ovarian changes during ovulation
 the oocyte in the dominant follicle completes its first meiotic
division
 local secretion of plasminogen activator and other cytokines
required for the process of ovulation is increased
 The oocyte is released from the follicle at the surface of the
ovary approximately 36 hours after the LH surge

•There is a close relation of follicular rupture and oocyte release to
the LH surge; as a result, measurements of serum or urine LH can
be used to estimate the time of ovulation in women
•Even before the oocyte is released, the granulosa cells
surrounding it begin to luteinize and produce progesterone.
•Progesterone acts rapidly to slow the pulse generator so that LH
pulses become less frequent by the termination of the surge.

Middle to Late Luteal Phase
• Progesterone secretion from the corpus luteum results in gradually rising
progesterone concentrations in the middle to late luteal phase
 This negatively inhibits and slows down LH pulses
• Inhibin A is also produced by the corpus luteum (peaks in the mid luteal
phase)
• Inhibin B secretion is virtually absent during the luteal pahse

The Uterus

•Histologic cycling of the endometrium can best be viewed in two
parts
The endometrial glands and
The surrounding stroma

• Endometrium
 Decidua functionalis
oSuperficial 2/3rd of the endometrium
o Composed of two parts
 Stratum spongiosum
Stratum compactum
oProliferates and ultimately shed with each cycle if pregnancy does
not occur

• Endometrium cont’d
 Decidua basalis
o Deepest region of endometrium
o Does not undergo significant monthly proiferations
o Source of endometrial regeneration after each menses

• Endometrial Stem cells: Do they exist?
The existence of endometrial stem cells was assumed but difficult to
document
 Evidences of their existence
oDiscovery of human epithelial and stromal cells that possess clonogenicity,
oEndometrial glandular epithelial cells obtained from endometrial biopsies of
women undergoing bone marrow transplants, express the HLA type of the
donor bone marrow

•Uterine cycle is divided into
Proliferative and
Secretory phases

Proliferative Phase
•At the beginning of the proliferative phase, the endometrium is
relatively thin (1--2 mm)
•The predominant change seen during this time is evolution of the
initially straight, narrow, and short endometrial glands into longer,
tortuous structures

•Histologically, these proliferating glands have multiple mitotic cells,
and their organization changes from a low columnar pattern in the
early proliferative period to a pseudostratified pattern before
ovulation
•Throughout this time, the stroma is a dense compact layer, and
vascular structures are infrequently seen

After menses, the decidua basalis is
composed of primordial glands and
dense scant stroma in its location
adjacent to the myometrium
The proliferative phase is
characterized by progressive mitotic
growth of the decidua functionalis in
preparation for implantation of the
embryo in response to rising
circulating levels of estrogen
By convention, the first day of
vaginal bleeding is called day 1 of
the menstrual cycle

Secretory Phase
• Secretory phase
 So named for the clear presence of eosinophilic protein – rich
secretory products in the glandular lumen
In the typical 28-day cycle, ovulation occurs on cycle day 14
 Within 48 to 72 hours ( Day 16 – 17) following ovulation, the
onset of progesterone secretion produces a shift in histologic
appearance of the endometrium to the secretory phase

In general, progesterone’s effects are antagonistic to those of
estrogen, and there is a progressive decrease in the endometrial
cell’s estrogen receptor concentration
As a result, during the latter half of the cycle, estrogen-induced
DNA synthesis and cellular mitosis are antagonized

•During the secretory phase
the endometrial glands form characteristic periodic acid–Schiff positive–staining,
glycogen-containing vacuoles
o These vacuoles initially appear subnuclearly and then progress toward the glandular
lumen
o The nuclei can be seen in the midportion of the cells and ultimately undergo apocrine
secretion into the glandular lumen, often by cycle day 19 or 20
o At postovulatory day 6 or 7 (Day 20 – 21), secretory activity of the glands is generally
maximal, and the endometrium is optimally prepared for implantation of the blastocyst

•The stroma of the secretory phase remains unchanged
histologically until approximately the seventh postovulatory day
(Day – 21), when there is a progressive increase in edema.
•Coincident with maximal stromal edema in the late secretory
phase, the spiral arteries become clearly visible and then
progressively lengthen and coil during the remainder of the
secretory phase.

•By around day 24, an eosinophilic-staining pattern, known as
cuffing, is visible in the perivascular stroma
•Eosinophilia then progresses to form islands in the stroma followed
by areas of confluence
•This staining pattern of the edematous stroma is termed
pseudodecidual because of its similarity to the pattern that occurs
in pregnancy

•Approximately 2 days (Day – 26) before menses, there is a
dramatic increase in the number of polymorphonuclear
lymphocytes that migrate from the vascular system
•This leukocytic infiltration heralds the collapse of the endometrial
stroma and the onset of the menstrual flow

Menses

Menses
•In the absence of implantation, glandular secretion ceases and an
irregular breakdown of the decidua functionalis occurs.
•The resultant shedding of this layer of the endometrium is termed
menses.
•The destruction of the corpus luteum and its production of estrogen
and progesterone is the presumed cause of the shedding.

•With withdrawal of sex steroids, there is a profound spiral artery
vascular spasm that ultimately leads to endometrial ischemia.
•Simultaneously, there is a breakdown of lysosomes and a release
of proteolytic enzymes, which further promote local tissue
destruction.
•This layer of endometrium is then shed, leaving the decidua basalis
as the source of subsequent endometrial growth.

•Prostaglandins are produced throughout the menstrual cycle and
are at their highest concentration during menses
•PGF2α is a potent vasoconstrictor, causing further arteriolar
vasospasm and endometrial ischemia.
PGF2α produces myometrial contractions that decrease local
uterine wall blood flow and may serve to expel physically the
sloughing endometrial tissue from the uterus.

Dating the Endometrium
•The changes seen in secretory endometrium relative to the LH
surge were thought to allow the assessment of the “normalcy” of
endometrial development.
•Since 1950, it was felt that by knowing when a patient ovulated, it
was possible to obtain a sample of endometrium by endometrial
biopsy and determine whether the state of the endometrium
corresponds to the appropriate time of the cycle.

•Traditional thinking held that any discrepancy of more than 2 days between chronologic and
histologic date indicated a pathologic condition termed luteal phase defect; this abnormality
was linked to both infertility (via implantation failure) and early pregnancy loss
•Evidence suggests a lack of utility for the endometrial biopsy as a diagnostic test for either
infertility or early pregnancy loss
•In a randomized, observational study of regularly cycling, fertile women, it was found that
endometrial dating is far less accurate and precise than originally claimed and does not
provide a valid method for the diagnosis of luteal phase defect

•Furthermore, a large prospective, multicenter trial sponsored by the
National Institutes of Health showed that histologic dating of the
endometrium does not discriminate between fertile and infertile women
•Thus, after half a century of using this test in the evaluation of the
subfertile couple, it became clear that the endometrial biopsy has no
role in the routine evaluation of infertility or early pregnancy loss.

Hormonal Variations

1. At the beginning of each monthly menstrual cycle, levels of gonadal
steroids are low and have been decreasing since the end of the
luteal phase of the previous cycle.
2. With the demise of the corpus luteum, FSH levels begin to rise, and a
cohort of growing follicles is recruited.
These follicles each secrete increasing levels of estrogen as they grow
in the follicular phase. The increase in estrogen, in turn, is the stimulus
for uterine endometrial proliferation.

3. Rising estrogen levels provide negative feedback on pituitary FSH secretion, which begins
to wane by the midpoint of the follicular phase.
 In addition, the growing follicles produce inhibin-B, which suppresses FSH secretion by
the pituitary.
 Conversely, LH initially decreases in response to rising estradiol levels, but late in the
follicular phase the LH level is increased dramatically (biphasic response).
4. At the end of the follicular phase (just before ovulation), FSH-induced LH receptors are
present on granulosa cells and, with LH stimulation, modulate the secretion of
progesterone

5. After a sufficient degree of estrogenic stimulation, the pituitary LH
surge is triggered, which is the proximate cause of ovulation that
occurs 24 to 36 hours later. Ovulation heralds the transition to the
luteal–secretory phase.
6. The estrogen level decreases through the early luteal phase from just
before ovulation until the midluteal phase, when it begins to rise again
as a result of corpus luteum secretion. Similarly, inhibin-A is secreted by
the corpus luteum.

7. Progesterone levels rise precipitously after ovulation and can be
used as a presumptive sign that ovulation has occurred.
8. Progesterone, estrogen, and inhibin-A act centrally to suppress
gonadotropin secretion and new follicular growth.
 These hormones remain elevated through the lifespan of the
corpus luteum and then wane with its demise, thereby setting
the stage for the next cycle.

Fertilization

• Fertilization
 It is the process during which a male gamete (sperm) unites
with a female gamete (oocyte ) to form a single cell (ZYGOTE)
Begins with a contact between the sperm & the ovum
Ends up with intermingling of the maternal and paternal
chromosomes

• Site of fertilization
Usually in the ampulla of the uterine tube
Ampulla is the longest and widest part
Fertilization may occur in other parts of tubes
Does not occur in the uterine cavity
Chemical signals from oocyte attract the sperms

• Phases of Fertilization
• 1- Passage of sperm through corona radiata, under the effect
of : hyaluronidase enzyme from sperms, tubal environment and
movement of tail of sperm
•2- Penetration of the zona pellucida by head of sperms through
acrosine enzyme from acrosome of one sperm.
•3- Fusion of the plasma membrane of the oocyte and that of the
sperm, so sperm’s plasma membrane remains behind

•4- Completion of the second meiotic division & formation of the female
pronucleus.
•5- Formation of the male pronucleus
•It is a swollen nucleus of the sperm
•Its tail is detached and degenerated.
• 6 - Zona reaction : it is a change in properties of zona pellucida that
makes it impermeable to other sperms.

•Results of Fertilization
1. Stimulates the penetrated oocyte to complete its 2nd meiotic
division
2. Restores the normal diploid number of chromosomes in the
zygote (46)
3. Determines the chromosomal sex of the embryo
4. Initiates cleavage (cell division) of the zygote

• Cleavage of a zygote
Consists of repeated mitotic divisions of the zygote
Rapid increase in the number of the cells
These smaller embryonic cells are called Blastomeres
Normally occurs in the uterine tube.

•It begins about 30 hours after
fertilization.
•Zygote divides into 2, then 4, then 8,
then 16 cells.
•Zygote lies within the thick zona
pellucida during cleavage.
•Zygote migrates in the uterine tube from
its lateral end to its medial end.
•Zona pellucida is translucent under light
microscope.

•When there are 12-32 blastomeres the
developing human is called MORULA.
•The Morula reaches the uterine cavity at this
stage.
•Spherical Morula is formed about 3 days after
fertilization.

• Formation of Blastocyst
The Morula reaches the uterine cavity by the 4th day after
fertilization, & remains free for one or two days.
Fluid passes from uterine cavity to the Morula
Now the Morula is called Blastocyst, its cavity is called
blastocystic cavity, its cells divided into Embryoblast &
Trophoblast.

BLASTOCYST
It is formed of :
(1) Trophoblast .
(2) Inner cell mass.
(3) Blastocyst cavity.

Implantation

• Blastocyst
 Preimplantation embryo of cell numbers 30 – 200
 4 days after gonadotropin surge
 3 days after ovulation

• Implantation
 Embeding of the blastocyst into the endometrial stroma
 Begins with the loss of zona pellucida
 1 – 3 days after the morula (8 cells) enters the uterine cavity
 Window of endometrial receptivity  Days 20 – 24 of 28 days
cycle

• Timing of implantation
 5 – 7 days after fertilization

• Messengers of a dialogue in between the endometrium and early
embryo
 Early pregnancy factor
 hCG
 Prostaglandin E2

• First hormonal evidence of implantation
 The appearance of hCG in maternal serum
o 8 – 9 days after ovulation

• Stages of Implantation
 Apposition
 Adhesion
 Penetration
 Invasion

• Secretions of the endometrium involved in implantation
 CSF -1
 LIF
 IL – 1

References
1. Hoffman, Schorge, Bradshaw, Halvorson, Schffer, Corton.
Williams Gynecology. 3rd ed. New York: McGrwa - Hill
Education; 2016.
2. Berek JS, Berek DL. Berek & Novak ’ s Gynecology. 15th ed. Vol.
22. Philadelphia: LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS
KLUWER business; 2012.
3. UpToDate 21.8
HALE TEKA, M.D., OBSTETRICIAN AND GYNECOLOGIST 93
Wednesday, December 4, 2019

Thank
you for
listening!

Additional Notes

The number of oocytes peaks in the fetus at 6 to 7 million by 20 weeks of gestation
Simultaneously (and peaking at the 5th month of gestation), atresia of the oogonia
occurs, rapidly followed by follicular atresia
At birth, only 1 to 2 million oocytes remain in the ovaries,
Of these, only 400 to 500 will ultimately be released during ovulation. By the time of
menopause, the ovary will be composed primarily of dense stromal tissue with only rare
interspersed oocytes remaining
At puberty, only 300,000 of the original 6 to 7 million oocytes are available for ovulation
Folliculogenesis

At the diplotene stage, a single layer of 8 to 10 granulosa cells surround the oogonia
to form the primordial follicle. The oogonia that fail to become properly surrounded
by granulosa cells undergo atresia.
A central dogma of reproductive biology is that in mammalian females there is no capacity for
oocyte production postnatally.
Because oocytes enter the diplotene resting stage of meiosis in the fetus and persist in this
stage until ovulation, much of the DNA, proteins, and messenger RNA (mRNA) necessary for
development of the preimplantation embryo is synthesized by this stage
The remainder proceeds with follicular development.
Thus, most oocytes are lost during fetal development, and the remaining follicles are steadily
“used up” throughout the intervening years until menopause.

Height: 2 – 5 cms
Wdith: 1.5 – 3 cms
Thickness: 0.5 – 1.5
cms
Weight: 5 – 10
grams
Three parts:
1. Cortex
2. Medulla
3. Hilum

•Th eovary develops from three major cellular sources:
1. Primordial germ cells,
oWhich arise from the endoderm of the yolk sac and
oDifferentiate into the primary oogonia;
2. Coelomic epithelial cells
oWhich develop into granulosa cells; and
3. Mesenchymal cells from the gonadal ridge,
oWhich become the ovarian stroma.

primoridal cells migrate from yolk sac into the
gonadal ridge to generate primary sex cords (6th
week of life) and undergo serious of mitotic divisions
Histologic sex differentitaion possible (1th week of
life)
Subset of oogonia enter meiosis to become primary
oocytes (12th week of life)
Primary oocyte surrounded by single layer of
flattened granulosa cells create primoridal follicle
Primordial germ cells identified in the yolk sac (3rd
week of life

primary oogonia enter meiosis in utero to become primary oocytes
These oocytes are arrested in development at prophase I during the first meiotic division
Meiotic division resumes at ovulation in response to the LH surge
Once again, the process is arrested, this time in the second meiotic metaphase
Meiosis is completed only if fertilization occurs

•The arrest of meiosis prior to ovulation is believed to be due to
production of an oocyte maturation inhibitor (OMI) by the
granulosa cells
• Meiosis is completed only if fertilization occurs

• Outcomes of completion of first meiotic division
 Production of a polar body which contains chromosomal
material but minimal cytoplasm
• Outcomes of completion of second meiotic division
 Formation of second polar body
 generation of preembryo with 46, XX or 46, XY karyotype

Preantral Follicle
•During the several days following the breakdown of the corpus luteum,
growth of the cohort of follicles continues, driven by the stimulus of FSH.
•The enlarging oocyte secretes a glycoprotein-rich substance, the zona
pellucida, which separates it from the surrounding granulosa cells except
for the aforementioned gap junction
•With transformation from a primordial to a preantral follicle, there is
continued mitotic proliferation of the encompassing granulosa cells.

•Simultaneously, theca cells in the stroma bordering the granulosa cells
proliferate
•Both cell types function synergistically to produce estrogens that are secreted
into the systemic circulation.
•At this stage of development, each of the seemingly identical cohort members
must either be selected for dominance or undergo atresia.
•It is likely that the follicle destined to ovulate was selected before this point,
although the mechanism for selection remains obscure.

Pre – ovulatory Follicle

Two – Cell, Two – Gonadotropin Theory

Ovulation
•The midcycle LH surge is responsible for a dramatic increase in local
concentrations of prostaglandins and proteolytic enzymes in the follicular wall
•These substances progressively weaken the follicular wall and ultimately allow a
perforation to form
•Ovulation most likely represents a slow extrusion of the oocyte through this
opening in the follicle rather than a rupture of the follicular structure
•Direct measurements of intrafollicular pressures were recorded and failed to
demonstrate an explosive event.

Luteal Phase
• Structure of Corpus Luteum
After ovulation, the remaining follicular shell is transformed into the primary regulator of the luteal phase:
the corpus luteum.
Membranous granulosa cells remaining in the follicle begin to take up lipids and the characteristic yellow
lutein pigment for which the structure is named.
These cells are active secretory structures that produce progesterone, which supports the endometrium
of the luteal phase. In addition, estrogen and inhibin-A are produced in significant quantities.

Unlike the process that occurs in the developing follicle, the basement membrane of the corpus
luteum degenerates to allow proliferating blood vessels to invade the granulosa-luteal cells in
response to secretion of angiogenic factors such as vascular endothelial growth factor
This angiogenic response allows large amounts of luteal hormones to enter the systemic
circulation.

Stromal Ovarian Cells
• Ovarian stroma
contains interstitial cells, connective tissue cells, and contractile cells
Of these, connective tissue cells provide structural support to the
ovary
Interstitial cells surrounding a developing follicle differentiate into
theca cells
Under gonadotropin stimulation, these cells increase in size and
develop lipid stores, characteristic of steroid-producing cells

Hilus Cells
• Hilus Cells
Another group of interstitial cells is present in the ovarian hilum and therefore
are known as hilus cells
These cells closely resemble testicular Leydig cells, and hyperplasia or
neoplastic changes in hilar cells may result in virilization from excess
testosterone secretion
The normal role of these cells is unknown, but their intimate association with
blood vessels and neurons suggest that they may convey systemic signals to
the remainder of the ovary

•The phases of the ovarian cycle are characterized as follows:
Follicular phase
o hormonal feedback promotes the orderly development of a single dominant follicle,
which should be mature at midcycle and prepared for ovulation.
o The average length of the human follicular phase ranges from 10 to 14 days, and
variability in this length is responsible for most variations in total cycle length.
Luteal phase
o the time from ovulation to the onset of menses has an average length of 14 days.

Summary

Puberty is marked by an increase in the pulsatile
secretion of GnRH from the hypothalamus.
GnRH stimulates the secretion of FSH and LH from
the gonadotroph cells in the anterior pituitary gland.
In girls, FSH stimulates the growth of ovarian
follicles and, in conjunction with LH, stimulates
production of estradiol by the ovaries.
Early in puberty, estradiol stimulates breast
development and growth of the skeleton, leading
to pubertal growth acceleration.
Later in puberty, the interplay between pituitary
secretion of FSH and LH and secretion of estradiol by
ovarian follicles leads to ovulation and menstrual
cycles.
The skeletal maturation induced by estradiol
eventually results in fusion of the growth plates and
cessation of growth.

Menstrual cycle, fertilization and implantation

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