Physiology of Menstrual Cycle

PHYSIOLOGY OF
MENSTRUAL CYCLE
Dr. Kanupriya Meena
R.N.T. Medical College, Udaipur
Dept. of Obstetrics and Gynaecology
Obgyn resident
PG3

WHAT IS MENSTRUAL CYCLE?
• 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.
• Normal limits: Frequency: 21-35 days
Duration: 3-8 days
Volume: 10-80 mL
• Menstrual cycle can be explained in two cycles which occur concurrently :
1.) Regular cyclical growth of ovarian follicles and release of egg each month – Ovarian
cycle
2.) Regular cyclical growth of endometrium and shedding – Uterine cycle

THE ENDOCRINE CYCLE
• The ovulatory menstrual cycle is the result of the integrated action of the hypothalamus, pituitary, ovary,
and endometrium. Like a metronome, the hypothalamus sets the beat for the menstrual cycle by the
pulsatile release of gonadotropin-releasing hormone (GnRH). GnRH pulses occur every 1-1.5 h in the
follicular phase of the cycle and every 2-4 h in the luteal phase of the cycle. Pulsatile GnRH secretion
stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone
(FSH). The pituitary gland translates the tempo set by the hypothalamus into a signal, LH and FSH
secretion.
• 1.) HYPOTHALAMIC HORMONE :
• Gonadotropin-releasing hormone (GnRH) (also called luteinizing hormone–releasing Hormone
hormone, or LHRH) is the controlling factor for gonadotropin secretion. It is a decapeptide produced by
neurons with cell bodies primarily in the arcuate nucleus of the hypothalamus. GnRH is normally
secreted in pulsatile manner (episodic bursts). It is delivered to the anterior pituitary through portal
vessels. Its secretion is inhibited by estrogen and progesterone which is secreted from ovary. GnRH
stimulates the release of both FSH and LH from pituitary.

• The continual pulsatile secretion of GnRH is necessary because GnRH has an extremely short half-life (only 2–4
minutes) as a result of rapid proteolytic cleavage. The pulsatile secretion of GnRH varies in both frequency and
amplitude throughout the menstrual cycle and is tightly regulated. The follicular phase is characterized by
frequent, small-amplitude pulses of GnRH secretion. In the late follicular phase, there is an increase in both
frequency and amplitude of pulses. During the luteal phase, however, there is a progressive lengthening of the
interval between pulses. The amplitude in the luteal phase is higher than that in the follicular phase, but it
declines progressively over the two weeks.
2.) ANTERIOR PITUITARY HORMONE : The gonadotropins FSH and LH are produced by the anterior
pituitary gonadotroph cells and are responsible for ovarian follicular stimulation.
• FSH is a water-soluble glycoprotein of high molecular weight and is secreted by the b-cells. FSH controls the
ripening of the primordial follicles, and in conjunction with the LH, it activates the secretion of oestrogen.
• Its activity builds up as the bleeding starts to cease reaches a peak around the seventh day of the cycle (40
ng/mL) and then declines to disappear around the 18th day. Another small peak occurs after ovulation, perhaps
as a result of a fall in the level of oestrogen in the premenstrual phase. The half-life of FSH is 4 h.
• Low FSH causes defective folliculogenesis and short or defective corpus luteal phase. Oestrogen suppresses
FSH secretion through negative feedback mechanism. It develops LH receptors in the granulosa cells.

• LH is a water-soluble glycoprotein of high molecular weight secreted by b-cells. LH pulse occurs
only during sleep initially, but later extends throughout the day. LH surge initiated by oestrogen
lasts for 48 h and is preceded by a small amount of progesterone 2 h earlier. LH level doubles in 2
h and the peak plateaus for 14 h before declining.
• Progesterone secretion begins 34 h after LH peak. In conjunction with FSH, it activates the
secretion of oestrogen, brings about the maturation of the ovum and causes ovulation. LH
stimulates the completion of the reduction division of the oocyte. Following ovulation, it produces
luteinization of the granulosa and the theca cells and initiates progesterone secretion.
• The LH surge precedes ovulation by 24–36 h (mean 30 h) and a minimum of 75 ng/mL is required
for ovulation. This time relationship of LH peak to ovulation is helpful in predicting the exact time
of ovulation in infertile women on gonadotropin therapy, making it possible to retrieve ova in in
vitro fertilization and to arrange for timely artificial insemination to enhance chances of
conception.
• LH stimulates the secretion of testosterone and androstenedione in the ovarian stroma (theca
cells), which diffuse into the follicular fluid and are aromatized into oestradiol.

• 3.) OVARIAN HORMONES
• Secreted in cyclical fashion in 2 phases – the follicular proliferative phase and the secretory
luteal phase.
• Ovaries secrete estrogen, progesterone, small amounts of androgen and peptides like inhibin
and activin needed for normal menstruation.
• They are mainly by theca and granulosa cells of ovary in follicular phase and from corpus
luteum in luteal phase.
• After ovulation, ovarian follicle is converted into corpus luteum which secretes large amount
of progesterone and small amounts of estrogen. This high progesterone levels exert negative
feedback effect on hypothalamus inhibiting GnRH release which in turn causes fall in LH
and FSH from anterior pituitary.
• If fertilisation does not occur, CL regresses to become corpus albicans with dramatic decline
in estrogen and progesterone levels leads onto menstruation.
• After the menstruation, the early part of follicular phase is stimulated by a rise in FSH
levels occurring due to fall in progesterone and estrogen level of the previous cycle and thus
the new cycle starts.

HYPOTHALAMO- PITUITARY-OVARIAN AXIS

.
• Several levels of feedback to the
hypothalamus exist and are known as the
long, short and ultrashort feedback loops.
• 1.) long loop feedback : peripheral gland
hormones (ovarian hormones) exert
feedback control on both hypothalamus and
pituitary. It is usually –ve but can
sometimes be +ve.
• 2.) short loop feedback : the effect of anterior
pituitary trophic hormones on the synthesis
or release of hypothalamic releasing or
inhibitory hormones. Thus, pituitary
gonadotropins (FSH and LH) inhibit GnRH
production and release from hypothalamus.
• 3.) ultrashort loop feedback : the
hypothalamic and pituitary hormones may
inhibit their own secretion and synthesis via
this control system.

OVARIAN CYCLE
• The phases of the ovarian cycle are characterized as follows:
• 1. Follicular phase—hormonal feedback promotes the orderly development of a
single dominant follicle, which should be mature at midcycle and prepared for
ovulation. 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.
• 2. Luteal phase—the time from ovulation to the onset of menses has an average
length of 14 days.

PRIMORDIAL FOLLICLE
 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 years.
 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 days
 First visible signs of development are
 Increase in the size of oocyte
 granulosa cells becoming cuboidal

PRE ANTRAL FOLLICLE
 Oocyte enlarges and is surrounded by a membrane, the zona pellucida.
 The granulosa cells undergo a multilayer proliferation as the theca layer continues to organize from
the surrounding stroma.
 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.
 FSH :
 initiates steroidogenesis (estrogen production) in granulosa cells and
 stimulates granulosa cell growth and proliferation

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
cumulus oophorus

THE TWO-CELL,
TWO-GONADOTROPIN THEORY
 The fundamental tenet of follicular development is the two-cell, two-gonadotropin theory. This theory states
that there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing
follicle.
 The aromatase activity of the granulosa cells is more than thecal cells.
 In human preantral and antral follicles,
 LH receptors are present only on the theca cells and
 FSH receptors only on the granulosa cells
 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 :- positive feedback
 (2) the effect of estrogen on pituitary secretion of FSH:- negative feedback.
 Serves to withdraw gonadotropin support from the other less developed follicles.
 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 secretion.
 High levels of estrogen induce the LH surge at midcycle, and high steady levels of estrogen lead to sustained
elevated LH secretion.
 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 hypothalamus.

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
autocrine-paracrine regulators.
 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.

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 hyperemic appearance.
 The oocyte proceeds in meiosis, approaching completion of
its reduction division.
 Approaching maturity, the preovulatory follicle produces
increasing amounts of estrogen.
 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
androgen superiority.
 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 FSH surge.
 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.

OVULATION
 A threshold of LH concentration must be
maintained for at least 14 to 27 hours in
order for full maturation of the oocyte tooccur.
 Usually the LH surge lasts 48 to 50 hours

LH, FSH, Progesterone, growth factors
Plasminogen activator synthesis (granulosa &theca cells)
Plasminogen Plasmin
Collagenase
Disrupts follicular wall

 Estradiol levels plunge as LH reaches its peak. This may be a consequence of LH
down-regulation of its own receptors on the follicle.
 Due to-
 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
 Estrogen can exert an inhibitory effect on P450c17 (aromatase enzyme)

LUTEAL PHASE
 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
luteolysis.
 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
 Endothelin-1
 inhibits luteal steroidogenesis,
 stimulates prostaglandin production in luteal cells.
 stimulates the release of TNF Alpha,which induces apoptosis.

THE LUTEAL-FOLLICULAR
TRANSITION
 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.

UTERINE CYCLE
 The changes in the endometrium will be discussed in five
phases:
(1)The menstrual endometrium
(2)The proliferative phase
(3)The secretory phase
(4)Preparation for implantation, and finally
(5)The phase of endometrial breakdown.

PROLIFERATIVE PHASE
 The glands :
 narrow and tubular, lined by low columnar epithelium cells.
 Mitoses
 Pseudostratification
 A continuous epithelial lining facing the endometrial cavityis
formed.
 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-thirdsof
the uterus, the usual site of blastocyst implantation.
 The endometrium grows from approximately 0.5 mm to 3.5to
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 cells.

SECRETORY PHASE
 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 endometrial cavity
- 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.

IMPLANTATION PHASE
 By 13 days postovulation, the endometrium has differentiated into three
distinct zones.
 1/4th of the tissue is the unchanged basalis, straight vessels and spindle- shaped stroma.
 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 increase in permeability under the influence of
steroids.

ENDOMETRIAL BREAKDOWN
 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 wane.
 The most prominent immediate effect of this hormone withdrawal is a modest shrinking of the
tissue height and spiral arteriole vasomotor responses.
 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 relaxation.
 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 stroma.
 During arteriolar vasomotor changes, red blood cells escape into the interstitial space.
Thrombin-platelet plugs also appear in superficial vessels.
 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 decidual cells.
 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
collagens;
 gelatinases that further degrade collagens;
 and stromelysins that degrade fibronectin, laminin, and glycoproteins
 Progesterone withdrawal from endometrial cells induces matrix metalloproteinase secretion.
 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 fibrinolysis
 PAI-1 exerts an important restraining action on fibrinolysis and proteolytic activity.
 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 collapses.
 The process is initiated in the fundus and extends throughout the uterus.
 In the end, the typical deflated, shallow, dense, menstrual endometrium results.

 Within 13 hours, the endometrial height shrinks from 4 mm to
1.25 mm.
 Menstrual flow stops as a result of the combined effectsof
 Prolonged vasoconstriction of the radial arteries and the spiral
arteries in the basalis,
 Tissue collapse,
 Vascular stasis,
 Estrogen-induced healing
 In contrast to postpartum bleeding, myometrial contractions are not important for
control of menstrual bleeding.

SUMMARY OF MENSTRUAL CYCLE
REGULATION
1) GnRH is produced in the arcuate nucleus of the hypothalamus and secreted in a
pulsatile fashion into the portal circulation, where it travels to the anterior pituitary.
2) Ovarian follicular development moves from a period of gonadotropin
independence to a phase of FSH dependence.
3) As the corpus luteum of the previous cycle fades, luteal production of progesterone
and inhibin A decreases, allowing FSH levels to rise.
4) In response to FSH stimulus, the follicles grow and differentiate and secrete
increasing amounts of estrogen and inhibin-B.
5) Estrogen stimulates growth and differentiation of the functional layer of the
endometrium, which prepares for implantation. Estrogens work with FSH in
stimulating follicular development.

6. The two-cell two-gonadotropin theory dictates that with LH stimulation, the ovarian theca cells will
produce androgens that are converted by the granulosa cells into estrogens under the stimulus of FSH.
7. Rising estrogen and inhibin levels negatively feed back on the pituitary gland and hypothalamus and
decrease the secretion of FSH.
8. The one follicle destined to ovulate each cycle is called the dominant follicle. It has relatively more
FSH receptors and produces a larger concentration of estrogens than the follicles that will undergo
atresia. It is able to continue to grow despite falling FSH levels.
9. Sustained high estrogen levels cause a surge in pituitary LH secretion that triggers ovulation,
progesterone production, and the shift to the secretory, or luteal, phase.
10. Luteal function is dependent on the presence of LH. However, the corpus luteum secretes estrogen,
progesterone, and inhibin-A, which serve to maintain gonadotropin suppression. Without continued
LH secretion, the corpus luteum will regress after 12 to 16 days. The resulting loss of progesterone
secretion results in menstruation.
11. If pregnancy occurs, the embryo secretes hCG, which mimics the action of LH by sustaining the
corpus luteum. The corpus luteum continues to secrete progesterone and supports the secretory
endometrium, allowing the pregnancy to continue to develop.

Physiology of Menstrual Cycle

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