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The

Menstrual Cycle | Obstetrics


THE MENSTRUAL CYCLE


Predictable, regular, cyclical, and spontaneous ovulatory
menstrual cycles are regulated by:
o Hypothalamic-pituitary axis
o Ovaries
o Genital Tract
Average cycle duration: 28 days
Average cycle range: 25-32 days

The Ovarian Cycle
1. Follicular or Pre-ovulatory Ovarian Phase
Average length: 10-14 days
The human ovary:
o At birth: 2,000,000 oocytes
o Puberty: 400,000 follicles
o Follicles are depleted at a rate of 1000
follicles/month until age 35
o Only 400 follicles are released (normal) during the
female reproductive life 99.9% of follicles
undergo atresia
GDF9 (Growth Differentiation Factor 9) and BMP-15
(Bone Morphogenetic Protein 15)
o Produced by the oocytes
o Regulates granulosa cell proliferation and
differentiation as the primary follicles grow
o Stabilizes and expands the cumulus oocyte complex
in the oviduct
Follicle-Stimulating Hormone (FSH)
o Required for further development of the large antral
follicles

o Cohort group of antral follicles that begin a phase


of semisynchronous growth based on their
maturation state
o Selection window FSH rise leading to follicle
development
Estrogen levels rise in parallel to the growth of the
dominant follicle and to the increase in the number of
granulosa cells (exclusive site of FSH receptor
expression)
After the appearance of the LH receptors, the
preovulatory granulosa cells begin to secrete
progesterone in small quantities
Preovulatory progesterone secretion positive
feedback on the estrogen primed pituitary to cause (or
augment) LH release
Early follicular phase:
o Granulosa cells produce inhibin B feedback on the
pituitary to inhibit FSH release
Late follicular phase:
o LH stimulates thecal cell production of androgens
(androstenedione) transfer to adjacent follicles
aromatization into estradiol
Growth of the dominant follicle increase in the
production of estradiol and inhibin decline in the
follicular phase FSH
Drop in FSH is the cause of the failure of other follicles
to reach the preovulatory status (Graafian follicle
stage) 95% of plasma estradiol is produced by the
dominant follicle (the one that will ovulate)
Contralateral ovary is relatively inactive

The Menstrual Cycle | Obstetrics


2. Ovulation
Increasing estrogen secretion by preovulatory follicles
onset of gonadotropin surge (good indicator of
ovulation)
Occurs 34-26 hours before the release of the ovum
from the follicle
LH secretion peaks at 10-12 hours before ovulation
stimulates the continuation of meiosis in the ovum +
release of the first polar body
Progesterone and Prostaglandin production by the
cumulus cells + GDF9 and BMP-15 activates
expression of genes essential to the formation of the
ECM by the cumulus complex
Expansion 20-fold increase in the cumulus complex
volume brought about by the outward movement of
the cumulus cells
LH-induced remodeling of the ovarian ECM release
of the mature oocyte and its surrounding cumulus
cells through the surface epithelium

LH controls theca cell


production
of
androstenedione
diffuses into the
adjacent granulosa
cells acts as
precursor for estradiol
biosynthesis

FSH controls the ability
of the granulosa cell
to convert
androstenedione to
estradiol.

3. Luteal or Postovulatory Ovarian Phase


Luteinization
o The development of the corpus luteum from the
Graafian follicle
o Hypertrophy of the theca-lutein and granulosa-
lutein cells increased capacity for hormone
synthesis
Breakdown of the basement membrane separating the
ganulosa-lutein and theca-lutein cells
Day 2 postovulation invasion of blood vessels and
capillaries into the granulosa cell layer
Factors contributing to the rapid neovascularization of
the avascular granulosa:
o Vascular Endothelial Growth Factor (VEGF),
produced in response to the LH secretion by the
theca-lutein and granulosa-lutein cells
Luteinizing Hormone
o Primary luteotropic factor responsible for corpus
luteum maintenance
o Extends the life span of the corpus luteum in normal
women (at least 2 weeks)

o Maintains corpus luteum by means of low-


frequency, high-amplitude pulses that are secreted
by the gonadotropes
Hormone secretion pattern of the Corpus Luteum
o Increased access to considerably more steroidogenic
precursors through blood-borne LDL-derived
cholesterol increased capacity to produce
progesterone (granulosa-lutein cells)
o Low LDL minimal progesterone secretion during
the luteal phase
o HDL contributes to progesterone production
Estrogen Pattern of Secretion
o After ovulation, estrogen levels decrease
secondary rise that reaches a peak of 0.25 mg/day at
the midluteal phase (17B-estradiol)
o Secondary decline in estradiol production follows
toward the end of the luteal phase
Ovarian Progesterone Production
o Peaks during the midluteal phase (25-50 mg/day)
o In pregnancy:
Corpus
luteum
continues
progesterone
production in response to hCG
Human Corpus Luteum
o Transient endocrine organ
o In the absence of pregnancy, regresses (luteolysis)
9-11 days after ovulation (apoptotic cell death)
o Luteolysis is in part due to the decreased levels of
circulating LH during the late luteal phase and
decreased LH sensitivity of luteal cells
o Endocrine effects (drop in circulating estradiol and
progesterone) are important for folliculat
development and ovulation
o CL regression and decline signals the
endometrium to initiate menstruation.

4. Estrogen and Progesterone Action
17B-estradiol
o Most biologically potent naturally-occurring
estrogen
o Secreted by granulosa cells of the Graafian
(dominant) follicle and luteinized granulosa cells of
the corpus luteum
Estrogen
o Essential hormonal signals where most events of the
menstrual cycle depend
o Action involves ERa and ERB (nuclear hormone
receptors)
o Regulates
follicular
development,
uterine
receptivity, or blood flow
Progesterone
o Actions are mediated through the progesterone
receptor types A and B (PRA and PRB)
o Enters cells by diffusion
o Evokes rapid responses in intracellular free calcium
levels

The Menstrual Cycle | Obstetrics


After ovulation, the


CL forms and both
theca-
and
granulosa-lutein
cells respond to LH.
Theca-lutein cells
continue
androstenedione
production while
the
granulosa-
lutein cells gets
increased capacity
to
produce
progesterone and
convert
androstenedione
into estradiol. LH
and hCG bind to
the same receptor and if pregnancy occurs, the hCG rescues the
corpus luteum.


The Endometrial Cycle
Cyclic changes that occur in the endometrium in
response to ovarian steroids
Phases:
o Proliferative
o Secretory
1. Proliferative or Preovulatory Endometrial Phase
The Endometrium
o Stratum functionalis (superficial layer)
Stratum compactum
Stratum spongiosum
o Stratum basalis
The deep layer where the stratum functionalis is
regenerated from
Follicular phase estradiol most important factor in
endometrial recovery after menstruation
Normal Range 5-7 days or 21-30 days
1st day of bleeding = 1st day of the cycle
2/3 of the functional endometrium is shed off after
menstruation
5th day of bleeding epithelial surface of the
endometrium is restored
Preovulatory endometrium characterized by
glandular, stromal, and vascular endothelial cells
Early Proliferative Phase
o Endometrium is <2 mm thick
o Glands are narrow, tubular structures that pursue
an almost straight and parallel course from the
basalis layer towards the endometrial cavity
o 5th cycle day mitotic figures in the glandular
epithelium are identified
o Mitotic activity persists up to the 16th or 17th day
(approx.. 2-3 days after ovulation)
o Absent extravascular or leukocyte infiltration in the
endometrium
o Re-epithelialization and angiogenesis are important
to stop endometrial bleeding. Both are dependent on
estrogen-regulated tissue growth

o Other pertinent factors:


Epidermal Growth Factor (EGF) and Transforming
Growth Factor a regulates epithelial cell growth
Estrogen and Fibroblast Growth Factor-9 (FGF-9)
increases stromal cell proliferation
VEGF causes angiogenesis through vessel
elongation in the basalis
Late Proliferative Phase
o Endometrium thickens due to glandular hyperplasia
and increased stromal ground substance (edema
and proteinaceous material)
o Prominent loose stroma
o Glands in the functionalis layer become widely
separated
o Glands in the basalis later are more crowded, with a
denser stroma
o Midcycle glandular epithelium becomes taller and
pseudostratified
o Microvilli in the surface epithelial cells increase the
surface area
o Cilia aids in movement of endometrial secretions

2. Secretory or Postovulatory Endometrial Phase
Constantly occurs at 12-14 days
Early Secretory Phase
o Estrogen-primed endometrium responds to rising
progesterone levels predictably
o Day 17 Glycogen accumulates in the basal portion
of the glandular epithelium subnuclear vacuole
and pseudostratification formation (1st sign of
histologically-evident ovulation)
o Day 18 vacuoles move to the apical portion of the
secretory nonciliated cells
o Day 19 secretory non-ciliated cells begin to secrete
glycoprotein and mucopolysaccharide contents into
the lumen; rising progesterone levels cessation of
glandular cell mitosis (it antagonizes estrogen
effects)
Mid- to Late-Secretory Phase
o Day 21-24 stroma becomes edematous
o Day 22-25 stromal cells surrounding the spiral
arterioles begin to enlarge; stromal mitosis apparent
Predecidual formation of the upper 2/3 of the
functionalis layer
Extensive coiling of the glands
Luminal secretions become visible
o Day 23-28 predecidual cells surround the spiral
arterioles
o Day 20-24 window of implantation
Decreased microvilli and cilia on the cell surfaces
Pinopods appear in preparation for blastocyst
implantation
Continuing growth and development of spiral
arterioles is seen
Spiral arterioles arise from radial arteries
(myometrial branches of the arcuate and
uterine vessels)

The Menstrual Cycle | Obstetrics


Essential for blood flow changes during


menstruation of implantation
Endometrium Dating
o Endometrial biopsy
o Luteal phase defect discrepancy by more than 2
days
o Failure of implantation and early pregnancy


3. Menstruation
In the absence of implantation, glandular secretion
ceases and the breakdown of the deciduas functionalis
occur
Death of the corpus luteum drop in progesterone
Luteal progesterone decrease menstruation is
initiated
Leukocyte infiltration key to endometrial and
extracellular matrix breakdown and repair of the
functionalis layer
Inflammatory tightrope ability of the macrophages
to assume phenotypes that vary from pro-
inflammatory and phagocytic to immunosuppressive
and reparative
Tissue
breakdown
and
restoration
occur
simultaneously during menstruation
Secretion of enzymes by the leukocytes in addition to
the proteases produced by endometrial stromal cells
initiate matrix degradation
Completion of tissue shedding microenvironment-
regulated changes promote repair and resolution
Anatomical Events
o Marked changes in endometrial blood flow
o Spiral artery coiling becomes severe resistance to
blood flow endometrial hypoxia
o Stasis becomes the primary cause of endometrial
ischemia and tissue degeneration
o Vasoconstriction precedes menstruation most
striking and constant event in the cycle
Limits menstrual blood loss
Prostaglandins and Menstruation
o Produced throughout the menstrual cycle, highest
during menstruation
o Progesterone withdrawal

Increases COX-2 expression increased


prostaglandin synthesis
Decreases 15-hydroxyprostaglandin expression
(degrades prostaglandin)
Net result: increased prostaglandin production
and prostaglandin-receptor density
o PGF2a vasoconstrictor produced by the
endometrium
o Prostaglandin causes:
Vasoconstriction
Myometrial contraction
Upregulation of proinflammatory responses
Activation of Lytic Mechanisms
o Protease activation degrades the endometrial
interstitial matrix
o Matric metalloproteases (MMP-1 and MMP-3)
released from the stromal cells and activate other
neutrophilic proteases
Origin of Menstrual Blood
o Arterial > Venous Bleeding
o Follows rupture of a spiral arterial hematoma
formation distention of the endometrium
rupture fissures develop in the functionalis layer
blood and tissue fragments begin to detach
o Arteriolar constriction stops the hemorrhage
o Partial tissue necrosis seals the vessel tips
o Endometrial surface is restored by growth of flanges
(collars) that form everted free ends of the
endometrial glands
Interval Between Menses
o Modal interval: 28 days 7 days
o Interval: 28 days 7 days
o Range: 21-35 days
o Duration: 2-6 days of flow
o Average Blood Loss: 20-60 mL

Education is what remains after one has forgotten everything he learned in


school.
Albert Einstein