[OBSTETRICS A] THE OVARIAN AND ENDOMETRIAL CYCLE
THE OVARIAN AND ENDOMETRIAL CYCLE
Aida V. San Jose, MD, FPOGS
**Bigger picture at the last page 
 Ovulation happens on day 14 of the cycle
 The OVARIAN CYCLE is divided into:
 Follicular or Preovulatory Phase (Day 1 to Day 14)
 Luteal or Postovulatory Phase (Day 14 to 28)
 The ENDOMETRIAL CYCLE is divided into:
 Proliferative Phase (Day 1 to Day 14)
 Secretory Phase (Day 14 to 28)
 The 2 cycles does not exactly begin at the same time
because the ovarian cycle likely begins 1 to 2 days
before day 1 of the endometrial cycle.
THE OVARIAN CYCLE
 The development of predictable, regular, cyclical and
spontaneous ovulatory menstrual cycles is regulated by
complex interactions of the hypothalamic-pituitary axis,
the ovaries and the genital tract
 We also call this the HPOE Axis  Hypothalamic-
Pituitary-Ovarian-Endometrium Axis
 Average duration of the menstrual cycle: 28 days (25 – 32
days)
FOLLICULAR (PREOVULATORY) OVARIAN PHASE
At birth 2 million oocytes present
At puberty 400,000 follicles present
Rate of depletion of follicle
1,000 follicles/month
per month until 35 years old
# of follicles ovulated during
400 follicles
the entire reproductive age
Percentage of follicles which
undergo atresia during 99.9 %
lifetime
 Reproductive life  30 to 35 years
 Atresia is due to apoptosis (natural cell death)
STAGES OF HUMAN FOLLICULAR DEVELOPMENT
 Gonadotropin–independent recruitment of primordial
follicles
 Gonadotropin-independent  Meaning, they are not
dependent on the gonadotropins (LH and FSH)
 Starts from resting pool to growth towards antral stage
 Under the control of growth differentiation factor 9
(GDF9), and bone morphogenic protein 15 (BMP-15)
produced by the oocytes, which regulate the proliferation
and differentiation of granulosa cells as the primary
follicles grow
 Since it is not gonadotropin-dependent, growth
and differentiation of follicles are influenced by
GDF9 and BMP-15 produced by the oocytes
 These are also called “Transforming Growth Factor
β”
GROWTH FACTORS:
- Also stabilize and expand the cumulus oocyte complex
(COC) in the oviduct
- Likely, the early steps in follicular development are
partly oocyte-controlled
- As antral follicles develop, surrounding stromal cells are
recruited to become theca cells
 Gonadotropin-dependent growth of large antral follicles
 Gonadotropin-dependent  Under the influence of
gonadotropin during the antral stage
 Involves FSH
 Enables a group of antral follicles (cohort) to begin a phase
of semisynchronous growth (selection window of the
ovarian cycle)
 Semisynchronous  Meaning, from the group of
antral follicles, only one will be chosen to become
the dominant follicle = Selection Window of the
Ovarian Cycle
 Only the follicles progressing to this stage develop the
capacity to produce estrogen
 Bulk of the estrogen will be coming from this
dominant follicle
LEA THERESE R. PACIS 1

 Follicular Phase
 Estrogen levels rise in parallel to growth of dominant
follicle and the increase in its number of granulosa cells
which are the exclusive site of FSH receptor expression
 Increase in FSH in the late luteal phase of the previous
cycle
- Stimulates an increase in FSH receptors
- Enable aromatization of the thecal cell-derived
androstenedione into estradiol
 FSH most likely increases about a day or two prior
to day 1 of the next cycle.
 This increase in the late luteal phase of the previous
cycle stimulates an increase in the FSH receptors 
This will enable aromatization of the thecal cell-
derived adrostenedione into estradiol by the action
of cytochrome P450
(Picture Above) 2-GONADOTROPIN, 2-CELL
HYPOTHESIS
 2-cell  Granulosa cell and Thecal cell
 2-gonadotropin  FSH and LH
 During the Follicular Phase of the Ovarian Cycle, LH
controls the theca cell production of
androstenedione  This androstenedione will
diffuse to the adjacent granulosa cell and will serve
as the precursor for estradiol biosynthesis
 During the Luteal Phase of the Ovarian Cycle, both
the theca-lutein cell and granulosa-lutein cell are
under the control of LH (in contrast to the
granulosa cell during the Follicular Phase, which is
under the control of FSH)  Theca-lutein cell
continues to produce androstenedione  Will
diffuse to the adjacent granulosa-lutein cell 
Undergo conversion to estradiol  The granulosa-
lutein cell has increased its the capacity to
synthesize progesterone and convert
androstenedione to estradiol
[OBSTETRICS A] THE OVARIAN AND ENDOMETRIAL CYCLE
 If fertilization happens and pregnancy occurs, LH
from the corpus luteum will be taken over by HCG
coming from the blastocyst. HCG, therefore,
rescues the corpus luteum during pregnancy. We
call this the Luteoplacental Shift which happens a
few weeks after fertilization.
 Initially, the corpus luteum supports the pregnancy
through the production of LH. But during the 6th-7th
week of gestation, the placenta takes over this
function.
In cases wherein one will be diagnosed with an
ovarian cyst during this period, we should defer
(unless it is an extreme emergency) the surgical
management for this cyst, especially if the it is
only an incidental finding and if the patient is
asymptomatic, because this ovarian cyst may
happen to contain the corpus luteum. If you
remove this ovarian cyst before the 6th or 7th
week of gestation, then it may result to abortion.
2-GONADOTROPIN, 2-CELL HYPOTHESIS:
 Granulosa cell – FSH
 Thecal cell – LH
 FSH induces the enzyme aromatase and expansion of the
antrum of the growing follicles
 The follicle within the cohort that is most responsive to
FSH is likely to be the first to produce estradiol and initiate
expression of LH receptors
 After the Appearance of LH Receptors
 The preovulatory granulosa cells begin to secrete small
quantities of progesterone which exert positive feedback
on the estrogen-primed pituitary to cause release of LH
 LH stimulates thecal cell production of androstenedione
 During the Early Follicular Phase
 Inhibin B produced by granulosa cells
 Negative feedback to the pituitary to inhibit FSH release
resulting to non-development of other follicles enabling
only 1 follicle to reach maturity
 Ovulation
 Gonadotropin Surge  Predicts ovulation
 34 – 36 hours before release of ovum from
Estrogen
the follicle
Surge
 A relative precise predictor of ovulation
 10 – 12 hours before ovulation
LH Surge  Stimulates the resumption of meiosis in the
ovum
 Lecture: LH surge is a relative precise predictor of
ovulation
LEA THERESE R. PACIS 2

 Current studies suggest that in response to LH, increased
progesterone & prostaglandin production by the cumulus
cells, and GDF9 & BMP-15 by the oocyte, activates
expression of genes critical to formation of hyaluronan-
rich extracellular matrix by the COC (Cumulus-Oocyte
Complex)
 When cumulus cells lose contact with each other & move
outward from the oocyte along the hyaluronan polymer
(Expansion)  Increase in volume of complex
 Luteal (Postovulatory) Phase
 After the ovum is released from the dominant follicle
during ovulation. What remains from the dominant
follicle will be converted to corpus luteum.
 Corpus luteum is said to be the remnant of the
dominant follicle after ovulation.
 Corpus luteum develops and the lifespan is maintained by
low-frequency, high amplitude pulses of LH secreted by
gonadotropes in the anterior pituitary
 Estrogen, just after ovulation, decrease followed by a
secondary rise at midluteal phase (0.25 mg/day of 17ß-
estradiol)
 17ß-estradiol  Most potent biologically active
type of estrogen
 Estrogen undergoes secondary decrease in estradiol
production toward the end of the luteal phase
 Progesterone production peaks during the midluteal
phase (25 to 50 mg/day)
 Human Corpus Luteum
 A transient endocrine organ that rapidly regresses 9 –11
days after ovulation
 9 –11 days after ovulation  Approximately 26th
day of the cycle
 Luteolysis results from the combination of decreased
levels of circulating LH in the late luteal phase and
decreased LH sensitivity of luteal cells
 Luteolysis = corpus luteum regression
 Luteolysis, characterized by the dramatic drop in
circulating levels of estradiol and progesterone, is critical
to allow the follicular development and ovulation of the
next ovarian cycle
 The previous cycle has something to do with the
subsequent cycle.
 It also signals the endometrium to initiate the molecular
events that will lead to menstruation
[OBSTETRICS A] THE OVARIAN AND ENDOMETRIAL CYCLE
 Estrogen and Progesterone Action
 Estrogen Effects
– The fluctuating levels of ovarian steroids  Direct cause
of endometrial cycle
– 17 ß-estradiol
o The most potent naturally-occurring estrogen
o Secreted by granulosa cells of the dominant follicle
& luteinized granulosa cells of corpus luteum
– Estrogen is the essential hormonal signal on which most
events in the normal menstrual cycle depend
– 2 Classic Hormone Receptors:
1. Estrogen Receptor α (ERα)
2. Estrogen Receptor ß (ERß)
– Both can exhibit distinct tissue expression
– Both receptors share robust activation by estradiol
– Have differences in binding affinities & have distinct and
overlapping functions
o Both are expressed in endometrium
– Interaction with steroid ligands  Estrogen receptor-
specific initiation of gene transcription
– Promotes synthesis of specific messenger RNAs and
specific proteins (estrogen & progesterone receptors)
 In addition to estrogen receptors synthesized by
estrogen, it also synthesizes progesterone
receptors.
This may be the explanation as to why in some
cases of abnormal bleeding (which is secondary
to unopposed estrogen stimulation,
particularly during menopause) estrogen is
given. Estrogen is given to prime the
endometrium and to help in the synthesis of
progesterone receptors so that progesterone
can act appropriately
 Pre-menopausal or after menopause,
women do not have progesterone anymore
since they are unable to ovulate because
their follicles have already been depleted.
 The usual treatment for this abnormal
uterine bleeding is by giving progesterone.
But this progesterone may not be able to act
if there is no prior estrogen priming because
estrogen helps in the synthesis of
progesterone receptors.
 Estrogen is said to be “pro-progesterone”
because it also synthesizes progesterone
receptors in addition to estrogen receptors.
Whereas, progesterone is said to be “anti-
estrogen” because it negates the activity of
estrogen.
– May act at endothelial cell surface to stimulate nitric
oxide production leading to its rapid vasoactive
properties
LEA THERESE R. PACIS 3

– Its ability to work in cell nucleus and at cell surface to
cause rapid changes in cell signaling molecules
 One explanation for the complex responses seen with
estrogen therapies
 Progesterone Effects
– Enters cells by diffusion and becomes associated with
progesterone receptors
– 2 Isoforms:
1. Progesterone Receptor Type A (PR-A)
2. Progesterone Receptor Type B (PR-B)
– Receptors have unique actions
– When PR-A & PR-B are co-expressed, PR-A can inhibit
PR-B gene regulation
– Inhibitory effect of PR-A can extend other steroid
receptors, including estrogen receptors
– Can evoke rapid responses such as changes in
intracellular free calcium levels
– The endometrial glands and stroma have different
expression patterns for these receptors that vary over
the menstrual cycle
– In the proliferative phase  The glands express both
receptors (PR-A and PR-B), and are involved with
subnuclear vacuole formation
– After ovulation  PR-B thru midluteal
– In contrast, the stroma and predecidual cells express
only PR-A throughout  Progesterone stimulate events
in stroma PR-A med
– PR-A may regulate the anti-proliferative effect of
progesterone during secretory phase
THE ENDOMETRIAL CYCLE
PROLIFERATIVE (PREOVULATORY) PHASE OF THE
ENDOMETRIUM
 The epithelial (glandular) cells, the stromal (mesenchymal)
cells, and the blood vessels of the endometrium replicate
cyclically in reproductive-aged women at a rapid rate
 Superficial endometrium shed and regenerated almost 400
times during the reproductive lifetime of most women
 Follicular-phase production of estradiol  Most important
factor in recovery of the endometrium
 2/3 of the functional endometrium  Fragmented and shed
during menstruation
[OBSTETRICS A] THE OVARIAN AND ENDOMETRIAL CYCLE
 Endometrium is divided into:
 Functionalis Layer = Superficial 2/3 of the
endometrium
– Shed during menstruation
– Regenerated during the proliferative phase of
the menstrual cycle
 Basalis Layer = Deeper 1/3 of the endometrium
– Provides the new endometrium following
menstruation
 Reepithelialization in progress even before menstrual
bleeding has ceased
 Even during the menstrual shedding,
reepithelialization of the endometrium is already in
progress. It is usually completed by the 5th day of the
endometrial cycle.
 Fifth day of the endometrial cycle  Epithelial surface of the
endometrium restored and revascularization of the
endometrium is in progress
 Preovulatory endometrium  Proliferation of vascular
endothelial, stromal and glandular cells
 Early Part of the Proliferative Phase:
 The endometrium thin, less than 2 mm in thickness
 Glands  Narrow
 Tubular structures pursue almost a straight and parallel
course from basal layer toward the surface of endometrial
cavity
 Mitotic figures in the glandular epithelium  Identified by
the fifth cycle day
 Mitotic activity in both epithelium and stroma persists
until day 16 to 17 (2-3 days after ovulation)
 Mitotic activity cease because of the anti-mitotic
activity of progesterone
 Blood vessels numerous and prominent, but no
extravascular blood or leukocyte infiltration in the
endometrium at this stage
 Leukocyte infiltration usually happens during the
premenstrual phase
 Re-epithelialization and angiogenesis  Important to the
cessation of endometrial bleeding at end of menstruation
 Estradiol appears to act by inducing growth factor gene
expression in stromal cells
 Late Proliferative Phase:
 Endometrium thickens due to glandular hyperplasia and
increase in stromal ground substance (edema &
proteinaceous material)
 Functionalis Layer  Glands & stroma are loose
 Basalis Layer  Glands are crowded; Stroma is dense
LEA THERESE R. PACIS 4

 At midcycle, surface epithelial cells acquire microvilli and
cilia
 Microvilli and cilia helps in the transport of
secretions in the endometrium  Secretions helps
nourish implantation of the blastocyst if there is
fertilization
 Day-by-day dating difficult
 “Dating” of the endometrium is usually done
during the secretory phase of the Endometrial
Cycle and not during the proliferative phase 
Proliferative phase can vary from 5-7 days to 20-30
days
 Proliferative Phase  Varies
 Secretory Phase  More or less constant (12-14
days)
SECRETORY PHASE
 Day 17
 Subnuclear vacuoles/Pseudostratification  First sign of
ovulation
 Day 19
 Release glycoprotein and mucopolysaccharide into lumen
 Glandular cell mitosis ceases
 17 -Hydroxysteroid Dehydrogenase  Converts estradiol
to estrone
 Estrone = Weaker type of estrogen
 One way by which progesterone acts as anti-estrogen
 Day 21 to 24
 Stroma becomes edematous
 Day 22 to 25
 Stromal cells surrounding the spiral arterioles enlarge
 Stromals cells  Later become the decidual cells
 Day 23 to 28  Presence of predecidual cells which
surround the spiral arterioles
 Extensive coiling of glands
 Secretion become visible
 Protrusions termed pinopods  Important in preparation
for blastocyst implantation
 Late Premenstrual Phase  Infiltration of stroma by
PMN’s  Pseudoinflammatory appearance
 Late Premenstrual Phase = Occurs 2-3 days before
day 1 of the next endometrial cycle
MENSTRUATION
 The midluteal-secretory phase  Critical branch point
in the development & differentiation of endometrium
 With rescue of corpus luteum  Decidualization
[OBSTETRICS A] THE OVARIAN AND ENDOMETRIAL CYCLE
 With luteolysis  Menstruation
 Critical branch point  Meaning, it can either end up
with fertilization and formation of the decidua OR if
fertilization did not take place, there will be luteolysis
and end up with menstruation
 Endometrial stromal and epithelial cells produce
Interleukin 8  Recruit neutrophil
 Monocyte chemotactic protein-1 (MCP-1) 
Chemoattractant for monocytes
 Infiltration of leukocytes  Key to initiation of extracellular
matrix breakdown of the functionalis layer
 Secretes metalloproteinase enzymes
 Classical study of Markee “Hypoxia Theory of Menses”
 Supercoiling of arteries  Endometrial ischemia and
tissue degeneration
 Corpus luteum regression leads to thinning of the
endometrium  Sudden disproportion in the
thickness of the endometrium and the arterioles 
These will lead to further coiling of the arteries 
Lead to ischemia and tissue degeneration
 INTENSE VASOCONSTRICTION precedes menstruation 
MOST STRIKING & CONSTANT EVENT observed in the
menstrual cycle
– Serves to limit blood loss during menstruation
 Interval between menses: 28 days (varies in general)
 28 ± 7 days  21 to 35 days
 Williams 24th Edition: 25-32 days
 PROSTAGLANDINS AND MENSTRUATION
 Prostaglandin F 2
– Vasoconstrictor  Initiation of menstruation
– Administration to women gives rise to dysmenorrhea
likely caused by myometrial contractions and
ischemia
– Administration to non-pregnant women 
Menstruation
 Female athletes who are scheduled to compete
usually use Prostaglandin F 2α to manipulate
their cycle and induce their period earlier
 VASOACTIVE PEPTIDES AND MENSTRUATION
 Endothelin-enkephalinase system regulates the spiral
artery blood flow
 Endothelins (ET-1, ET-2, ET-3)  Small, 21-amino acid
peptides
 ET-1  Potent vasoconstrictor
 Endothelins  Degraded by enkephalinase
 Enkephalinase  Localized in endometrial stromal cells
LEA THERESE R. PACIS 5

 Increase blood levels of progesterone after ovulation
 ORIGIN OF MENSTRUAL BLOOD
 Both arterial and venous in origin
 Arterial > Venous
 Begin by rupture of an arteriole of a coiled artery and
formation of hematoma
 Intense vasoconstriction  Rupture of vessel 
Hematoma formation
 Superficial endometrium distended then ruptures
 Fissures develop in adjacent functionalis layers and blood
and fragments of tissue are detached
 Hemorrhage stops when arterioles are again constricted
 Surface of endometrium restored by growth of the
flanges, or collars that form everted free ends of uterine
glands
 Flanges  Located in the basalis layer
 Flanges increase in diameter very rapidly, continuity of the
epithelium reestablished by fusion of the edges of these
sheets of migrating thin cells
DECIDUA OF THE ENDOMETRIUM
 Highly modified endometrium of pregnancy
 If a woman becomes pregnant, you call its
endometrium the DECIDUA.
 Decidualization  Dependent on estrogen and
progesterone and factors secreted by the implanting
blastocyst during trophoblast invasion
DECIDUAL STRUCTURES
 Decidua Basalis
 Directly beneath the site of blastocyst implantation
 Decidua Capsularis
 Overlying the enlarging blastocyst, separating it from the
rest of the uterine cavity
 Prominent on the 2nd month of pregnancy
 Covered with single layer of flattened epithelial cells w/o
glands
[OBSTETRICS A] THE OVARIAN AND ENDOMETRIAL CYCLE
 Internally, avascular extraembryonic fetal membrane –
Chorion Laeve
 Decidua Parietalis
 Remainder of uterus
 If fused with capsularis = Decidua Vera (14-16 weeks)
3 LAYERS OF DECIDUA PARIETALIS AND BASALIS
 Zona Compacta – Surface
Form the functionalis layer
 Zona Spongiosa – Middle
 Zona Basalis – Remains after delivery, gives rise to new
endometrium
DECIDUAL REACTION
 Completed only with blastocyst implantation
 Endometrial stromal cells enlarge to form polygonal or
round decidual cells
 Decidual cells form from the stromal cells
 Usually start around the spiral arterioles
 Nuclei  Round and vesicular
 Cytoplasm  Clear slightly basophilic, surrounded by
translucent membrane
 Decidual Cells  Lined by pericellular membranes
DECIDUAL BLOOD SUPPLY
 Capsularis  Blood supply is lost as the embryo-fetus grows
 Parietalis  Spiral arteries persists
 Spiral arterioles or arteries to decidua basalis  Invaded by
the cytotrophoblasts
 Walls of the vessels in the basalis are destroyed  Not
responsive to vasoactive agents
 Walls of the vessels in the basalis lose the smooth
muscle layer  Therefore, it does not respond to
vasoactive agents
 Fetal chorionic vessels  Responsive to vasoactive agents
DECIDUAL HISTOLOGY
 The primary cellular components of decidua  True
decidual cells differentiated from the stromal cells & bone
marrow-derived cells
 Large Granular Lymphocytes (LGLs)  Small, round cells, a
particular type of natural killer lymphocyte
 NITABUCH LAYER  Zone of fibrinoid degeneration
 If decidua is defective  Placenta Accreta, Nitabuch
layer is usually absent
 Nitabuch layer is usually absent in patients with
prior procedures at the lower uterine segments
Patients with prior low segment cesarean section
and now in current pregnancy have placenta
previa are more likely to have placenta accrete
because of the absence of this Nitabuch layer.
LEA THERESE R. PACIS 6
 [OBSTETRICS A] THE OVARIAN AND ENDOMETRIAL CYCLE

 ROHR STRIA  Superficial inconsistent deposition of fibrin 10,000 ng/mL  In the amniotic fluid, during the 20th-
at the bottom of intervillous space and surrounding the 24th week 350 ng/mL  In the fetus
anchoring villi  150-200 ng/mL  In maternal plasma
 Arachidonic Acid  Attenuates rate of Prolactin secretion
DECIDUAL PROLACTIN PRODUCTION  ET-1, IL-1, IL-2 and Epidermal Growth Factor  Decreases
 hPL (Placental Lactogen)  Produced by Prolactin secretion
syncitiotrophoblast  ROLE:
 Decidual Prolactin  Product of same gene that encodes for 1. Regulating immunological functions in the tissue during
prolactin secreted by the anterior pituitary pregnancy
 Amino acid sequence of prolactin in both tissues is identical 2. Regulation of angiogenesis that occur during
 Prolactin in Amnionic Fluid: implantation
3. Role in solute & water transport across the
 Prolactin in the decidua is mostly secreted into the chorioamnion
amniotic fluid.

LEA THERESE R. PACIS 7