Transcript Menstruation & ovulation

Menstruation &
ovulation
PHYSIOLOGY OF MENSTRUAL
CYCLE
The normal menstrual cycle is divided
into:
 1. The ovarian cycle.
 2. The uterine cycle.

THE OVARIAN CYCLE

The changes that occur in the ovary
during each cycle can be divided into
three stages: (1) The follicular phase (day
1 to 13), (2) Ovulatory phase (day 13 to
15) and (3) The luteal phase (day 15 to
28).
1.

The Follicular phase:
During the follicular phase, certain number of
follicles start to grow and some of them will pass from
the stage of primordial follicle to the stage of preantral
follicle, and usually few of them can pass to the antral
follicle stage of which one only succeeds to continue
through the pre-ovulatory follicle stage. In each of
these stages, there are many cellular, histological,
hormonal and functional changes that occur with
interaction between the gonadotropins and the ovarian
steroid hormones.
A.

The primordial follicle:
During the intrauterine life, the ovarian
differentiation starts in-between the 6th and the 8th
week by proliferation and multiplication of the germ
cells to reach a huge number (6-7 millions) around the
20th week. The germ cells stop mitotic division and
start meiosis under the effect of secretions of the
mesonephric tubules-derived cells "Rete cells" called
meiosis inducing substance. Passing through the early
stages of meiosis, the oocytes will be arrested at the
prophase of meiosis and become surrounded by a
layer of perivascular cells that are both mesenchymal
and epithelial in origin to form the primordial follicles.
Failure of achieving this coating by the granulosa cells
would lead germ cell to complete meiosis and die with
marked reduction of the germ cell population. This
process requires the presence of two X chromosomes
and so, in 45XO chromosomal pattern of Turner's
syndrome, gonadal dysgenesis occurs.


The primordial follicle is composed of oocyte arrested in
the diplotene stage of meiotic prophase, surrounded by
a single layer of pregranulosa cells (germinal epithelial)
resting on a basement membrane separating it from an
outer less organized matrix of pretheca cells
(mesenchymal cells). The rest of mesenchymal cells not
utilized in primordial follicle formation is noted in the
interstices between follicles, forming the primitive
ovarian stroma.
The process of follicular maturation is described as a
Continuum. It means that (The initial stages of
follicular growth occur during all physiological conditions
without any external stimulation). Each follicle seems to
have a genetic code for the timing at which it may
resume growth. The number of follicles that resumes
growth at any point of time is dependent on the size of
the residual pool of follicles in both ovaries and if the
residual pool is changed dramatically at any time, the
remaining follicles will rescheduled their readiness to
resume growth according to the new situation.


The first visible sign that the follicle resumes growth is that
the granulosa cells become cubical rather than squamous in
shape. Mitosis appears in the granulosa cells, the oocyte
expands and starts to secrete the zona pellucida (ZP). The
overall diameter of the primordial follicle is about 50 and
the oocyte is about 20 . Gap junctions develop between
surrounding granulosa cells and the oocyte to establish a
metabolic and electric linkage that will persist at ovulation.
Not all granulosa cells are receptor +ve, so activation
signals, protein kinase and cyclic AMP can pass from
receptor +ve granulosa cells to receptor -ve cells.
Once the primordial follicle resumes growth, the process
is irreversible, so if the situation is favorable, it would
passes to the next stage, otherwise, atresia is the definitive
fate. So the number of follicles in the ovaries is reduced
dramatically as time passes. The general pattern is initial
growth followed by atresia which is interrupted at the
beginning of the cycle during menses or even during the
last very few days of the previous cycle where a group of
emerging follicles is exposed, responds to the rising peptide
hormones stimulation ( withdrawal of the -ve feedback as
the CL degenerates) and is propelled to further growth.

The maximum number ( 6-7 millions ) is present at the
20th week of intrauterine life, of which 2 millions are
present at birth. No similar rate of depletion of the germ
cell mass is seen again, and there is evidence that the
major mechanism for this loss is by elimination through
the surface of the ovary into the peritoneal cavity. At the
onset of puberty, the germ cell mass has been reduced
to 300,000. During the next 30-45 years of reproductive
life, these units will be depleted further to a point at
menopause where follicles are almost completely
depleted. As 300-500 follicles would grow enough to
reach the ovulation phase, for each of them close to
1,000 will pursue abortive growth periods of variable
length.
B.


The Preantral Follicle:
Once growth is initiated, the follicle passes to the preantral
stage where the oocyte enlarges to reach a size of 80 ( same
size till ovulation, limited by the ZP ). The granulosa cells undergo
multilayer proliferation and the theca cells begins to organize
from the surrounding stroma with the development of its own
newly formed blood vessels. The overall diameter of the follicle at
this stage is about 200.
The growth in this stage is dependent on the gonadotropin
stimulation. LH acts mainly on the theca cells to start
steroidogenesis and the production of androgens mainly
testosterone and androstenedione. These androgens may pass
directly to the blood stream, but also some of it will back-diffuse
toward the granulosa cell layer where it is aromatized by the
granulosa cells under the effect of FSH. FSH not only stimulates
the conversion of androgens to estrogen but also propels follicles
to the antral stage by stimulating granulosa cell mitosis.
Together, FSH and estrogen increase the FSH receptors content
of the follicle with a resulting snowballing effect on follicle growth
and differentiation.

Androgen plays a delicate role to determine the
fate of the follicle. The presence of moderate
amounts of androgen in the follicle not only acts
as a substrate but also via androgen specific
receptor- stimulates its aromatization to
estrogen while excessive androgen would act as
anti-estrogen to inhibit aromatization leading to
androgen accumulation converted to 5-reduced
form which can not be converted to estrogen ,
so, the follicle becomes androgenic and
ultimately atretic.
C.

Antral Follicle:
As the follicle continues its growth under the
combined effect of FSH and estrogen, follicular fluid
accumulates in the intercellular spaces to form CallExner bodies and coalescing together to form the
characteristic follicular cavity "The Antrum" . The
antrum provides a specific hormonal environment for
the oocyte and the avascular granulosa cell layer
which is different from that of the serum and the other
follicles. The oocyte now bulges in the antrum being
surrounded by few layers of granulosa cell called
cumulus oophorus which attaches the oocyte to the
rest of the granulosa cell. The theca cell layer is
differentiated to well organized highly vascular theca
interna and less organized less vascular theca externa.

The antral follicle is characterized by the highest level of granulosa
cell proliferation, highest rate of FSH activity through huge number
of FSH receptors, and so the greatest ability to convert androgen to
estrogen making the antral follicle an estrogen-dominant follicle
with accumulation of FSH and estrogen in the antrum. This is
accompanied by a high degree of theca cell layer vascularization
which allows a preferential delivery of FSH and LH to this follicle.
The successful conversion to an estrogen-dominant follicle marks
the selection of the follicle destined to ovulate "the dominant
follicle", a process by which, except in rare exception, only one
follicle ovulates each cycle. The natural selection of the dominant
follicle is evident by day 7 of the cycle, although the process of
selection started at an earlier stage when one of the primordial
follicles has good synchronization between its timed resumption of
growth and the elevated level of FSH seen during the last few days
of the previous cycle.

This emerging dominant follicle produces about 95% of
the entire ovarian secretion. Within the antral follicle,
estrogen interacts with FSH to help maturation of the
dominant follicle, while estrogen released in the
circulation has a -ve feedback effect on the production
and release of FSH from the anterior pituitary leading to
a gradual drop in circulating FSH level. The drop in FSH
level would reduce aromatase activity in less mature,
less vascularized follicles and reduce granulosa cell
proliferation and activity promoting accumulation of
androgen thereby inducing irreversible atretic changes.
The dominant follicle is immune from the drop in FSH as
it has its own reservoir of FSH in the antrum with the
highest granulosa cell mass and the highest degree of
FSH receptors. So a wave of atresia among smaller
follicles is seen in parallel to the rise of circulating
estrogen produced from the dominant follicle.
D.


Preovulatory Follicle:
At this stage the follicle attains a big size, it
measures 20 mm or more. The granulosa cells enlarge
and attain lipid inclusion, while the theca cells are
highly vascularized with even more luteinization.
The oocyte resumes the nuclear component of
meiosis I. It passes from the late stages of the
prophase to the metaphase, anaphase and finally to the
telephase of meiosis I. It is at this stage when the
haploid number of chromosomes is produced as one
pair of the chromosomes together with a little
cytoplasm forms the first polar body that lies free inside
the zona pellucida, while the second pair with the rest
of the cytoplasm forms the secondary oocyte. Meiosis I
is completed during this stage and the secondary
oocyte enter meiosis II immediately before ovulation.
Meiosis II is only completed at the entry of the sperm at
the time of fertilization.
It is at this stage when the hypothalamic-pituitary ovarian interaction is
at the most critical point with great synchrony and harmony:
 Estrogen, mainly from the dominant follicle, reaches a high level
and it should reaches a level of 200 pg/ml or more in the plasma to
be maintained for at least 50 hours in order to produce the positive
feedback on the pituitary which induces the LH surge at midcycle.
The peak value of estrogen is reached 24-36 hours before ovulation
while FSH declines to a nadir level.
 LH starts to rise 32-38 hours before ovulation and reaches a peak
value 10-12 hours before it. Acting upon its own receptor which
were induced by the combined effect of FSH and estrogen, LH starts
luteinization of the granulosa cells resulting in the production of
progesteron within the microenvironment of the preovulatory follicle
24-48 hours before ovulation. Gonadotropins released at midcycle
are characterized with high bioactivity and longer half life with
increased content of sialic acid.
 Progesterone in very small amounts facilitates the positive feedback
response of the pituitary to threshold level of estrogen with
enhanced pituitary response to GnRH. In addition to this,
progesterone is responsible for the FSH surge at midcycle.


FSH has a midcyclic surge as LH but of much lesser
amplitude which serve to ensure that a full complement
of LH receptors is in place in the granulosa cells.
Androgens are also produced from the ovary at this
stage. The theca component of the other follicles which
fail to achieve full maturity, return to their origin as a
component of the ovarian stroma. They retain their
ability to respond to LH stimuli with the production of
androgen in the ovarian stroma. The plasma
androstenedione rises by 15% and testosterone by 20%
at midcycle. This rise in androgens acts locally to assure
and complete the wave of atresia in the non-dominant
follicles and may has a systemic effect to increase lipido
at midcycle.
2.

Ovulation:
Ovulation or follicular rupture is not due to increased intra-follicular
pressure. The escape of the ovum is preceded by separation of the
oocyte-cumulus cell mass from the rest of the follicle to float freely in the
antral fluid with massive increase in the amount of the fluid. The escape
of the ovum is associated with degenerative changes of the collagen in
the follicular wall which occurs just prior to ovulation. This is
accompanied by completion of the oocyte maturation and luteinization.
The midcyclic LH surge is the main stimulus to ovulation, but it should be
synchronized with oocyte maturation and other morphological and
functional changes within the dominant follicle. AS the main stimulus for
the LH surge is the high estrogen level produced by the dominant follicle,
it is the follicle itself that determines the proper timing of ovulation. In
addition to LH, the FSH surge, estrogen and progesterone all play a role
in the process of ovulation through manipulating the activity of several
non steroid products in the follicle, this may include:
a)
b)
c)
d)
LH induced rise in cyclic-AMP overcomes the effect of oocyte
maturation inhibitor (OMI) and luteinization inhibitor (LI) which
are two non steroid products of the follicle present in the follicular
fluid and serve to inhibit premature oocyte maturation and
luteinization.
LH and progesterone stimulate proteolytic enzymes (collagenase
and plasmin), resulting in the digestion of collagen in the follicular
wall. This may be mediated via the production of prostaglandins E
and F which may act to free lysosomal enzymes.
Prostaglandins may also stimulate the contraction of smooth
muscles which is present in the ovary.
FSH is a good stimulator for the release of plasminogen activators
which are responsible for the activation of plasminogen to
plasmin. FSH stimulates the synthesis of hyaluronic acid whose
accumulation is necessary in the separation of the oocytecumulus cell mass from the rest of the follicle.

The midcyclic increase in LH is short-living and it
shortly ends with a decline in the level of LH.
The exact mechanism is not yet fully known, but
it may be due to exhaustion of the LH storage in
the pituitary, -ve feedback of LH itself on the
GnRH pulse generator, down regulation of GnRH
receptors, or loss of the +ve feedback stimulus
as estrogen level plunges as LH reaches its peak
with a precipitous drop in circulating estrogen
level.
3.

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Luteal phase:
After ovulation and escape of the oocyte with the cumulus cell
mass to the peritoneal cavity, dramatic morphological changes
occurs in the remaining part of the follicle within the next 2-3
days converting it to the corpus luteum. The name is derived
from deposition of lutein, a yellow pigment of fat cells and egg
yolk, inside the granulosa cells which become vacuolated and in
the theca-lutein cells differentiated from the surrounding theca
and stromal cells.
Another very important anatomical change is the penetration
of the granulosa cells for the first time by blood capillaries from
the underlying theca-lutein layer, with filling of the cavity with
blood. Vascularization reaches its peak 8-9 days after ovulation.
This change is very important to deliver LDL to the granulosa cells
from which they extract cholesterol needed for steroidogenesis.
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The cells of the corpus luteum which have been prepared during the
follicular phase by FSH and estrogen and have a great number of LH
receptors produces great amounts of both estrogen and
progesteron under LH stimulation. Continuos LH stimulation at low
level is needed to maintain the steroid production by the CL.
Progesterone plasma level reaches its peak level 8 days after the LH
surge.
Progesterone acts centrally through the hypothalamus to
suppress gonadotropin production, and locally it suppress new
follicular growth in the ovary containing the CL. This effect is
mediated by depletion of estrogen receptors which is needed to
support early follicular differentiation. So during the next cycle,
usually the dominant follicle will be present in the contralateral
ovary.
The duration of the luteal phase is consistently close to 14
days from the LH surge to menses. In the absence of pregnancy,
the CL would decline within 9-11 days after ovulation with decline in
the steroid production. Luteolysis is induced by the high level of
estrogen reached in the second half of the luteal phase. This effect
is mediated by estrogen stimulated production of prostaglandins
within the ovary which uncouple the LH receptor complex from the
adenylate cyclase enzyme across the lipid bilayer of the cell
membrane. IB pregnancy occurs, HCG, produced from the chorion
starts to rise 9 days after ovulation to rescue the CL from
regression.
THE ENDOMETRIUM
(UTERINE) CYCLE
The histology of the adult endometrium:
 The endometrium can be divided into an upper
2/3 functionalis layer and lower 1/3 basalis layer
on the basis of morphology and function.
 The purpose of functional layer is to prepare for
implantation of blastocyst. It is the site for (1)
proliferation, (2) secretion and (3) menstruation.
 The purpose of basalis layer is to provide the
regenerative endometrium following menstrual
loss of functionalis.
The histologic changes are based on
two parts:
 Endometrial glands.
 Stroma.
I.


Proliferative phase:
In the proliferative phase, tissue components (glands including
endothelial cells, stromal cells) demonstrate proliferation, which
peaks on days 8-10 of the cycle, corresponding to peak estradiol
levels in the circulation and maximal estrogen receptor
concentration in the endometrium. This proliferation is marked by
increased mitotic activity and increased nuclear DNA and
cytoplasmic RNA synthesis, that is most intense in the functionalis
layer in the upper two-thirds of the uterus, the usual site of
blastocyst implantation.
At the beginning, the endometrium is relatively thin (1-2 mm). The
initially straight narrow and short endometrial glands changes to
longer tortuous structure. The organization changes: low columnar
pattern early proliferative (5th day of the cycle) to a pseudostratified before ovulation (12th day of the cycle); the stroma is a
dense compact layer throughout this time. Vascular structure is
infrequently seen.
II.


Secretory phase:
The corpus luteum produces large quantities of progesterone which
induces secretory changes in the glands and swelling of stromal cells.
There is a rich blood supply and the capillaries become sinusoidal with
little intervening stroma.
The first histologic sign that ovulation has occurred is the appearance of
subnuclear intracytoplasmic glycogen vacuoles in the glandular epithelium
on cycle days 17-18. Giant mitochondria and the "nucleolar channel
system" appear in the gland cells. Individual components of the tissue
continue to display growth, but confinement in a fixed structure leads to
progressive tortuosity of glands and intensified coiling of the spiral vessels.
These structural alterations are soon followed by active secretion of
glycoproteins and peptides into the endometrial cavity. Transudation of
plasma also contributes to the endometrial secretions. The peak secretory
level is reached 7 days after the midcycle gonadotropin surge, coinciding
with the time of blastocyst implantation.


Of note the endometrial height is fixed at roughly its
preovulatory extent (5-6 mm) despite continued
availability of estrogen. Epithelial proliferation ceases 3
days after ovulation. This restraint or inhibition is
believed to be induced by progesterone.
Implantation phase (Late Secretory); ie 7th - 13th post
ovulation (21th - 27th of cycle) whereby the distended
tortuous secretory glands have been most prominent
with little intervening stoma. The time of implantation is
in days 21-22 of the cycle. The predominant morphologic
feature is edema of endometrial stroma secondary to the
estrogen- and progesterone-mediated increase in
prostaglandin production. By day 13-14, post-ovulatory:
the endometrium is divided into 3 distinct zones: 1/4
unchanged basalis, 1/2 stratum spongiosum, 1/4
stratum compactum superficial layer.
III.

Menstrual phase:
The menstrual endometrium is a relatively thin but dense tissue. It
is composed of the stable, nonfunctioning basalis component and
a variable, but small, amount of residual stratum spongiosum.The
menstrual endometrium is a transitional state bridging the more
dramatic proliferative and exfoliative phases of the cycle. Its
density implies that the shortness of height is not entirely due to
desquamation. Collapse of the supporting matrix also contributes
significantly to the shallowness. Nevertheless, as much as twothirds of the functioning endometrium is lost during menstruation.
The more rapid the tissue loss, the shorter the duration of flow.
Delayed or incomplete shedding is in association with heavier flow
and greater blood loss
Menstruation (Bleeding) mechanism:
 The unique features of primate females who menstruate is the existence of
spiral arteries (end arteries,with no anastomosis) supplying the superficial
layer of the endometrium (funtionalis layer), thus making the superficial
layer of the endometrium vulnerable to ischaemia, but also facilitating
hemostasis.
 In the proliferative phase, the spiral arterioles grow upwards from the basal
to more superficial layers of the endometrium, where a capillary network
develops.
 In the luteal phase, there is a marked increase in length and coiling of the
spiral arterioles which will become more dilated.
 Premenstrually, the endometrial glands empty secretions, the fluid from the
stroma is resorbed, the endometrium shrinks (deflated), and the spiral
arterioles become even more coiled up to 8 loops. At the same time, gaps
appear between the endothelial cell of the spiral arterioles and the
associated thin walled veins and leucocytes migrate through the gaps into
the stroma which appears to be undergo disintegration.
Progesterone has a stabilizing effect and estrogen labilizing effect on
lysosomes in the endometrium. The withdrawal of progesterone preceding
menstruation probably causes breakdown of lysosomes and release of
phsopholipase A2. This in turn causes the formation of large amounts of
arachidonic acid from phospholipids in the cell wall and initiates the
prostaneid cascade and the synthesis of PGF2 and PGE2 and PGI2. The
sudden increase of prostaglandins, particularly PGF2 is probably
responsible for the spasmodic contraction of the spiral arterioles and for
menstruation.
 Immediately before menstruation, the spiral arteries constrict intensely for a
period of 4-24 hours and then dilate with a massive extravasation of
erythrocytes into the stroma of endometrium.
 Blood initially spurts from the open end of spiral arterioles but normally
stops rapidly. Bleeding occurs from the coalesced blood lakes and from the
torn ends of capillaries and veins, bleeding from the latter being slower and
continuing longer. Approximately 75% of menstrual blood is arterial and
25% is venous. Though the proportion may change in women with
menorrhagia, only about one-quarter of the total endometrium is shed; the
majority involutes and is reabsorbed, as in animal species which do not
menstruate.
 Menstrual blood contains aggregations of erythrocytes, degraded and
exhausted platelets, small amounts of fibrin and large amounts of fibrin
degradation products, suggesting that the haemostatic plugs and any blood
clots that may form undergo fibrinolysis and rapidly disintegrate. An excess
of fibrinolytic activity in the endometrium might well impair haemostatic
plug formation in the spiral arterioles and would provide a ready
explanation for excessive menstrual blood loss.

Menstrual blood stoppage mechanism (Haemostasis):
 Hemostatic plug function of aggregated platelets and fibrin in the
spiral arterioles, which is small and incomplete compared with those
in skin wounds with onion skin like allowing intermittent blood flow
before complete occlusion.
 Vasoconstriction of spiral arteries together with swelling of
endothelial cells which completely occlude the arterioles occurs in
the 2nd day of menstruation and is considered the most important
mechanism controlling menstrual blood. Prostaglandins play vital
part.
 Re-epithelization commences from the basal glands, proceeds
rapidly, and is usually completed by third or fourth day, which
depends on the rate of estrogen stimulation, which in turn, depends
on the rate of growth of the follicles developing in the ovaries. It
starts from the region of the isthmus and cornual recesses of the
ostea of the fallopian tube. Furthermore, the stromal layer
contributes important autocrine and paracrine factors for growth
and migration, mainly in response to injury rather than hormonal
effect as hormone levels are at their nadir.
The uterus as an endocrinal organ:
 The uterus is a dynamic as many endometrial products had been
verified. Lipids as Prostaglandins, Thromboxanes, Leukotrienes has
been identified to be secreted from stromal & endometrial cell with
various functions (see below). Cytokines as Interleukin-la,
lnterleukin-1B, lnterleukin-6, Interferon-g, Colony-stimulating factor1, Tumor necrosis factor-a Leukemia,-inhibiting factor were also
identified. List of other peptides secreted from endometrial cell with
various functions as enzymes & enzymes inhibitors, angiogenic,
vasoactive , hemostatic & growth factors includes : [ Prolactin,
Relaxin, Prorenin and rennin, Endorphin, Endothelin-1,Corticotropinreleasing hormone, Fibronectin, Uteroglobin, Lipocortin-1,
Parathyroid hormone-like protein, Integrins, Epidermal growth
factor family [EGF / Heparin-binding EGF / TGF-a ], Insulin-like
growth factor family [IGF-l / IGF-ll / IGFBPs1-6 ] , Platelet-derived
growth factor, Transforming growth factor-B, Fibroblast growth
factor, Vascular endothelial growth factor ].
Role of Prostaglandins:
 In the proliferative phase the endometrium synthesizes equal
amounts of PGF2 and PGE2 1:1, but in the luteal phase the level of
PGF2 progressively increases under the influence of estradiol and
progesterone 2:1 in menstrual fluid, so that vasoconstriction and
platelet - aggregatory action predominates. The myometrium
produces considerable amounts of PGI2 synthesized from
endoperoxides produced in the endometrium which diffuse to
myometrium, producing vasodilation and inhibiting platelet
aggregation.
 In normal menstruation, it is postulated that the PGF2 synthesized
in the endometrium first produces vasoconstriction of spiral
arterioles, and as a result, an increased proportion of the
endoperoxides is produced from arachidonic acid by prostaglandin
synthetase deviated into the myometrium, which, then produces a
surge of PGI2. This surge may then diffuse back into the
endometrium, producing the dilatation which follows the
vasoconstriction of spiral arterioles immediately preceding the onset
of menstruation.

At the end of the non-fertile cycle,
endoperoxides generated from free arachidonic
acid, released from membrane phospholipid
stores by the action of phospholipase A2, are
converted predominatly to prostaglandin F2Endoperoxides may also be transported to the
myometrium, where they are converted to
prostacyclin. Prostacyclin of myometrial origin
may act to prevent platelet aggregation and
stimulate vasodilation within the endometrium at
menstruation.
Role of Leukotrines:
 They are produced predominantly by leucocytes.
Excessive infiltration of the endometrium with
leucocytes is seen in menorrhagia with IUDs,
and the degree of menstrual blood loss is
roughly proportional to the degree of infiltration.
Excessive production of leukotrines is
responsible for IUCD menorrhagia, if the
arachidonic acid is deviated from the cyclooxygenase to the lipoxygenase pathway.
Enzymes & uterus:
 The endometrium and cervix are sites of marked
fibrinolytic activity and plasminogen activators have been
demonstrated in the myometrium, endometrium and
menstrual blood. The concentration of plasminogen
activators in menstrual blood is maximal on the first day
of bleeding and is higher in women with excess
menstrual blood loss. It is also much higher in samples
collected from the uterus than from the vagina,
suggesting that the activators are rapidly consumed and
explaining why clots may form in the vagina but rarely
do so in the uterus.
Endometrial Cycle: Clinical prospective:
 A normal menstrual cycle last from 21 to 35 days with 2 to 6 days of
flow & an average blood loss of 20-60ml. In the extremes of
reproductive age, menstrual cycles are characterized by a higher
percentage of anovulatory or irregularly timed cycles. The diagnosis
and management of abnormal menstrual function must be based on
an understanding of the physiologic mechanisms involved in the
regulation of the normal cycle.
 Primary dysfunctional bleeding (PDB), including essential
menorrhagia, probably results from a number of different factors,
including disturbances in eicosanoid metabolism and in fibrinolytic
and lysosomal enzyme systems of the endometrium. This
disturbance may be primarily in the endometrium or secondary to
endocrine changes originating in the ovary, pituitary and
hypothalamus.
 Excessive menstrual blood loss (MBL) could be due to the increased
formation of lysosomes with an increased synthesis of
phospholipase A2, arachidonic acid and prostaglandin at
menstruation as is believed to occur in ovulatoryDUB. Marked
increase in both plasminogen activators and in fibrinolytic activity
plasmin in menstrual blood in case of DUB particularly with IUDs.
This is reversed by anti-fibrinolytic drugs Tranexamic acid.



Interaction between thrombin formation and fibrinolysis of
hemostatic plugs and the action of prostanoids including PGI2 and
TXA2 and that the blood clotting fibrinolytic and prostanoid systems
are closely linked.
Clinical implication of Endometrial dating: The precise nature of the
histologic changes that occur in secretory endometrium relative to
LH surge allows the assessment of the “normalcy” of endometrial
development. Any large discrepancy (more than 2-day lag time) is
termed a Luteal phase defect & has been linked to both failure of
implantation & early pregnancy loss. To perform such diagnostic
test, determine ovulation timing then take an endometrial biopsy
10-12 days postovulation.
Also note the clinical implication of endometrial thickness (height)
by vaginal US.
The cervical cycle:
 Progesterone raises the tone of the muscles of the
isthmus and internal os so the cervical 'sphincter' is
tighter and more competent during the luteal than
during the follicular phase.
 The glandular elements proliferate during the follicular
phase and the epithelial cells become taller. Under the
influence of oestrogens the glands actively secrete a
mucus which will stretch into threads measuring more
than 6.5 cm, and even 10-15 cm, at the time of
ovulation. Spinnbarkeit is the basis of the thread test for
estrogen in circulation. During the follicular phase the
cervical mucus absorbs water and salts and, when
allowed to dry, deposits crystals of sodium chloride and
potassium chloride in a characteristic pattern which
suggests the fronds of a fern (see diagnostic
procedures).
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At the time of ovulation, the secretion is so profuse that
it may be noticeable as a vaginal discharge – the
“ovulation cascade”. Its special character at this time
makes for its easy penetration by spermatozoa. This
property is related to its low content of protein.
During the luteal phase, the cervical glands become
more branched and their secretion changes its physical
and chemical properties. The mucus becomes more
viscous and forms a more secure cervical plug. It loses,
its ability to stretch without breaking and resists
penetration by spermatozoa. These changes are brought
about by progesterone and are related to an increase in
the amount of protein in the mucus and to the presence
of phospholipids.
The vaginal cycle:
 The cyclical changes occur in the vaginal epithelium are
better seen in smears of desquamated cells. The
unstimulated vagina shows relatively small basal type
cells with healthy nuclei. These and intermediate
basophil forms are also seen in vaginal smears taken in
the early follicular phase. The fully oestrogemc smear,
evident during the late follicular phase, contains a
preponderance of large cornified epithelial cells with
pyknotic nuclei. These stain pink with eosin. During the
luteal phase the smear shows evidence of increased
desquamation, many of the cells having rolled edges,
and is characterized by the reappearance of clumps of
intermediate cells and the presence of leucocytes. The
maturation index, which is the percentage of superficial,
intermediate and parabasal cells in a vaginal smear is
used as a measure of the levels of hormones in
circulation. It is a useful guide but is not so precise as
assaying the hormones in blood.
Cyclical changes in the tube:
 The muscle of the fallopian tube behaves like the
myometrium in that it shows increased movement about
the time of ovulation. This is an estrogen effect. The
increased cilial activity at that time. These changes are
timed to propel the ovum towards the uterus.
 The follicular phase is marked by slight proliferation, and
this continues up to the premenstrual phase when it
regresses. During menstruation there is further
shrinkage and slight shedding of the surface epithelium.
 The secretory activity of the tubes is also cyclical, being
highest just before ovulation and in response to
oestrogen. Progesterone may also play a part in this but
the consensus of opinion is that hormone reduces the
amount of the secretion.