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Dr Anusha Rao P
Menstruation is a visible manifestation of cyclic, physiologic
uterine bleeding due to shedding of the endometrium following
invisible interplay of hormones mainly through H-P-O axis.
Frequency: 24-38 days
Regularity: +/- 2-20 days
Duration: 4-8 days
Volume: 5-80 mL
Menstrual cycle can be explained in two cycles which occur
• The ovarian cycle and
• The uterine cycle
The Ovarian Cycle consists of
The follicular phase and
The luteal phase
The Uterine Cycle consists of
The proliferative phase and
The secretory phase
Originate in the Endoderm
Migrate to the genital ridge at 5-6weeks
Maximum at 16 – 20 wks : 6 – 7 million
At Birth : 2 million
At Pubery : 0.3 to 0.5 million
Only 400 – 500 follicles ovulate during a woman’s reproductive
The primordial follicle is nongrowing and consists of an oocyte,
arrested in the diplotene stage of meiotic prophase, surrounded
by a single layer of spindle-shaped granulosa cells.
The initial recruitment and growth of the primordial follicles is gonadotropin
independent and affects a cohort over several months
The total duration of time to achieve pre ovulatory status is approximately 85
First visible signs of development are
Increase in the size of oocyte
granulosa cells becoming cuboidal
Gap junctions composed of channels formed by arrangement of
proteins known as Connexins –
up regulated and kept open by FSH and
down regulated and closed by LH
The Pre antral Follicle
Oocyte enlarges and is surrounded by a membrane, the zona
The granulosa cells undergo a multilayer proliferation as the theca
layer continues to organize from the surrounding stroma.
The granulosa cells of the preantral follicle synthesizes all 3 classes of
Estrogens are produced more than androgens or progestins
An aromatase enzyme system converts androgens to estrogens and is a
factor limiting ovarian estrogen production.
Aromatization is induced or activated through the action of FSH.
initiates steroidogenesis (estrogen production) in granulosa
stimulates granulosa cell growth and proliferation
The Antral Follicle
Under the influence of estrogen and
FSH, there is an increase in the
production of follicular fluid.
Oocyte and the surrounding granulosa
cells are nurtured in this follicular fluid
The granulosa cells surrounding the
oocyte are now designated the
The aromatase activity of the granulosa cells is more than
In human preantral and antral follicles,
LH receptors are present only on the theca cells and
FSH receptors only on the granulosa
LH stimulates thecal cells to produce androgens that can then
be converted, through FSH-induced aromatization, to
estrogens in the granulosa cells.
As the follicle emerges, the theca cells are characterized by their
expression of P450c17, the enzyme step that is rate limiting for the
conversion of 21-carbon substrate to androgens.
Increasing expression of the aromatization system (P450arom) is a
marker of increasing maturity of granulosa cells.
The presence of P450c17 only in theca cells and P450arom only in
granulosa cells is an impressive evidence confirming the two-cell,
two-gonadotropin explanation for estrogen production
Selection of the Dominant Follicle
The process of conversion of a single follicle to a estrogen
dominant follicle depends on
(1) a local interaction between estrogen and FSH within the follicle,
(2) the effect of estrogen on pituitary secretion of FSH:- negative
Serves to withdraw gonadotropin support from the other less
The first event in the process of atresia is a reduction in FSH
receptors in the granulosa layer
A wave of atresia among the lesser follicles,
is seen to parallel the rise in estrogen.
Lower GnRH pulse frequencies favor FSH secretion, and
higher GnRH pulse frequencies favor LH secretion.
Low levels of estrogen enhance FSH and LH synthesis and
storage, have little effect on LH secretion, and inhibit FSH
High levels of estrogen induce the LH surge at midcycle, and
high steady levels of estrogen lead to sustained elevated LH
Low levels of progesterone acting at the level of the pituitary
gland enhance the LH response to GnRH and are responsible
for the FSH surge at midcycle.
High levels of progesterone inhibit pituitary secretion of
gonadotropins by inhibiting GnRH pulses at the level of the
Inhibin, Activin, and Follistatin
This family of peptides is synthesized by granulosa cells in
response to FSH and secreted into the follicular fluid and
ovarian venous effluent.
They are expressed in many tissues through out the body as
Inhibin is an important inhibitor of FSH secretion.
Activin stimulates FSH release in the pituitary and augments
FSH action in the ovary.
Follistatin suppresses FSH activity by binding to activin.
Blocks the synthesis and secretion of FSH,
Prevent the up-regulation of GnRH receptors by GnRH,
Reduce the number of GnRH receptors present,
At high concentrations, promote the intracellular degradation of
The Preovulatory Follicle
Granulosa cells in the preovulatory follicle
enlarge and acquire lipid inclusions
And theca becomes vacuolated and richly
vascular, giving the preovulatory follicle a
The oocyte proceeds in meiosis,
approaching completion of its reduction
Approaching maturity, the preovulatory
follicle produces increasing amounts of
Estrogen peaks approximately 24 to 36
hours prior to ovulation.
The onset of the LH surge occurs when the peak levels of
estradiol are achieved.
In providing the ovulatory stimulus to the selected follicle, the
LH surge seals the fate of the remaining follicles, with their
lower estrogen and FSH content, by further increasing
LH promotes luteinization of the granulosa in the dominant
follicle, resulting in the production of progesterone
After adequate estrogen priming, progesterone facilitates the
positive feedback response.
And in the presence of subthreshold levels of estradiol can
induce a characteristic LH surge.
When administered before the estrogen stimulus, or in high
doses (achieving a blood level greater than 2 ng/mL),
progesterone blocks the midcycle LH surge.
Progesterone at midcycle is significantly responsible for the
Thus ensures completion of FSH action on the follicle,
especially making sure that a full complement of LH receptors
is in place in the granulosa layer.
As products of thecal tissue are androgens, the increase in
stromal tissue in the late follicular phase is associated with a
rise in androgen levels.
- for atresia of lesser follicles and for libido
Estradiol levels plunge as LH reaches its peak. This may be a
consequence of LH down-regulation of its own receptors on the
High LH causes supression of steroidogenesis
Low midcycle levels of progesterone exert an inhibitory action
on further granulosa cell multiplication, and hence the drop in
Estrogen can exert an inhibitory effect on P450c17(aromatase
Luteinization and the corpus luteum:
granulosa cells increase in size and assume a characteristic
vacuolated appearance associated with the accumulation of a
yellow pigment , lutein.
theca lutein cells may differentiate from the surrounding theca
and stroma to become part of the corpus luteum.
Angiopoietin-1 binds to the endothelial Tie-2 receptor & inc.
expr. Of VEGF + LH -> Angiogenesis
Angiopoietin-2, leads to vascular breakdown that accompanies
Vascularization of the granulosa layer is essential to allow LDL-
cholesterol to reach the luteal cells to provide sufficient
substrate for progesterone.
By day 8 or 9 after ovulation, a peak of vascularization is
reached, associated with peak levels of progesterone and
estradiol in the blood.
The leukocytes in the corpus luteum secrete cytolytic
enzymes, prostaglandins, and growth factors involved in
angiogenesis, steroidogenesis, and luteolysis.
Endothelin-1 is a mediator of luteolysis
Luteal cell population is composed of two distinct cell types,
large and small cells.
Large cells are derived from granulosa cells and
the small cells from theca cells.
The small cells are the most abundant.
Steroidogenesis takes place in the large cells,
Small cells contain LH and hCG receptors.
LH/hCG receptors are absent on the large cells,
The corpus luteum rapidly declines 9 to 11 days after ovulation.
The regression of luteal cells is induced by the estradiol
produced by the corpus luteum.
This action of estrogen is mediated by nitric oxide.
The final signal for luteolysis, however, is prostaglandin F2
alpha, produced within the ovary in response to the locally
synthesized luteal estrogen.
Prostaglandin F2Alpha stimulates the synthesis of endothelin
inhibits luteal steroidogenesis,
stimulates prostaglandin production in luteal cells.
stimulates the release of TNF Alpha,which induces apoptosis.
The demise of the corpus luteum results in a nadir in the circulating levels
of estradiol, progesterone, and inhibin.
The decrease in inhibin-A removes a suppressing influence on FSH
secretion in the pituitary.
The decrease in estradiol and progesterone allows a progressive and
rapid increase in the frequency of GnRH pulsatile secretion and a removal
of the pituitary from negative feedback suppression.
The removal of inhibin-A and estradiol and increasing GnRH pulses
combine to allow greater secretion of FSH compared with LH, with an
increase in the frequency of the episodic secretion.
The increase in FSH is instrumental in rescuing approximately a 70-day-
old group of ready follicles from atresia, allowing a dominant follicle to
begin its emergence.
The changes in the endometrium will be discussed in five
(1) The menstrual endometrium
(2) The proliferative phase
(3) The secretory phase
(4) Preparation for implantation, and finally
(5) The phase of endometrial breakdown.
The Proliferative Phase
The glands :
narrow and tubular, lined by low columnar epithelium cells.
A continuous epithelial lining facing the endometrial cavity is
All of the tissue components 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
Changes are most intense in the functionalis layer in the upper two-thirds of
the uterus, the usual site of blastocyst implantation.
The endometrium grows from approximately 0.5 mm to 3.5 to
5.0 mm in height
Restoration of tissue constituents has been achieved by
estrogen-induced new growth as well as incorporation of ions,
water, and amino acids.
An important feature of this estrogen-dominant phase of
endometrial growth is the increase in ciliated and microvillous
The endometrium now demonstrates a combined reaction to
estrogen and progesterone activity.
Epithelial proliferation ceases 3 days after ovulation.
Total endometrial height is fixed at roughly its preovulatory
extent (5-6 mm) despite continued availability of estrogen. This
limitation is due to :
Progesterone interference with estrogen receptor expression
stimulation of 17beta-hydroxysteroid dehydrogenase and
sulfotransferase, which convert estradiol to estrone sulfate
(which is rapidly excreted from the cell)
Tissue components continue to display growth, but confinement in a fixed structure leads
to progressive tortuosity of glands and intensified coiling of the spiral vessels.
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.
These structural alterations are soon followed by
- active secretion of glycoproteins and peptides into the
-Transudation of plasma
-immunoglobulins obtained from the circulation
The peak secretory level is reached 7 days after the midcycle gonadotropin surge,
coinciding with the time of blastocyst implantation
By 13 days postovulation, the endometrium has differentiated into three
1/4th of the tissue is the unchanged basalis, straight vessels and spindle-
The midportion (approx 50% of the total) is the lace like stratum
spongiosum,loose edematous stroma with tightly coiled spiral vessels and
dilated glandular ribbons.
the superficial layer of the endometrium (about 25% of the height) called the
stratum compactum, which has become large and polyhedral stromal cell,
forming a compact, structurally sturdy layer.
The subepithelial capillaries and spiral vessels are engorged
At the time of implantation, on days 21-22 of the cycle, the predominant
morphologic feature is edema of the endometrial stroma , due to inc in
permeability under the influence of steroids
In the absence of fertilization, implantation, and the consequent
lack of hCG from the trophoblast, the fixed lifespan of the corpus
luteum is completed, and estrogen and progesterone levels
The most prominent immediate effect of this hormone withdrawal
is a modest shrinking of the tissue height and spiral arteriole
The following vascular sequence occurs
With shrinkage of height, blood flow within the spiral vessels
diminishes, venous drainage is decreased, and vasodilation ensues.
Thereafter, the spiral arterioles undergo rhythmic vasoconstriction and
Each successive spasm is more prolonged and profound, leading
eventually to endometrial blanching.
Within the 24 hours immediately preceding menstruation, these
reactions lead to endometrial ischemia and stasis.
White cells migrate through capillary walls, extending throughout the
During arteriolar vasomotor changes, red blood cells escape into the
interstitial space. Thrombin-platelet plugs also appear in superficial
The prostaglandin content (PGF2 alpha and PGE2) in the secretory
endometrium reaches its highest levels at the time of menstruation.
The vasoconstriction and myometrial contractions associated with the
menstrual events are mediated by prostaglandins from perivascular
cells and the potent vasoconstrictor endothelin-1, derived from stromal
In the first half of the secretory phase, acid phosphatase and
potent lytic enzymes are confined to lysosomes, stabilized by
progesterone, which are released with waning of it’s level.
These active enzymes will digest their cellular constraints,
leading to the release of prostaglandins, extravasation of red
blood cells, tissue necrosis, and vascular thrombosis
Endometrial tissue breakdown also involves a family of
enzymes, matrix metalloproteinases
The metalloproteinases include
collagenases that degrade interstitial and basement membrane
gelatinases that further degrade collagens;
and stromelysins that degrade fibronectin, laminin, and
Progesterone withdrawal from endometrial cells induces matrix
In a nonpregnant cycle, metalloproteinase expression is
suppressed after menses by increasing estrogen levels.
Progesterone withdrawal is associated with an increase in
VEGF receptor concentrations in the stromal cells.
Although the VEGF system is usually involved with
angiogenesis, in this case these factors are involved in the
preparation for menstrual bleeding, perhaps influencing the
expression of matrix metalloproteinases.
Eventually,Leakage occurs as a result of diapedesis, and finally,
interstitial hemorrhage occurs due to breaks in superficial
arterioles and capillaries.
As ischemia and weakening progress, the continuous binding
membrane is fragmented, and intercellular blood is extruded into
the endometrial cavity.
New thrombin-platelet plugs form intravascularly upstream at the
shedding surface, limiting blood loss.
Increased blood loss is a consequence of reduced platelet
numbers and inadequate hemostatic plug formation.
Menstrual bleeding is influenced by activation of clotting and
PAI-1 exerts an important restraining action on fibrinolysis and
Blood loss is also controlled by constriction of the spiral
arteries, mediated by the perivascular cells, myofibroblasts that
surround the spiral arteries.
Myofibroblasts respond to progesterone withdrawal by
expressing prostaglandins and cytokines, causing cycling
vasoconstriction and vasodilation
Thrombin generation in the basal endometrium in response to
extravasation of blood is essential for hemostasis.
The basalis endometrium remains during menses, and repair
takes place from this layer.
This endometrium is protected from the lytic enzymes in the
menstrual fluid by a mucinous layer of carbohydrate products
that are discharged from the glandular and stromal cells.
A natural cleavage point exists between basalis and
spongiosum, and, once breached, the loose, vascular,
edematous stroma of the spongiosum desquamates and
The process is initiated in the fundus and extends throughout
In the end, the typical deflated, shallow, dense, menstrual
Within 13 hours, the endometrial height shrinks from 4 mm to
Menstrual flow stops as a result of the combined effects of
Prolonged vasoconstriction of the radial arteries and the spiral
arteries in the basalis,
In contrast to postpartum bleeding, myometrial contractions are
not important for control of menstrual bleeding.