The menstrual cycle is regulated by the hypothalamus, pituitary gland, and ovaries. It typically lasts 28 days and is divided into the follicular phase and luteal phase. During the follicular phase, follicle stimulating hormone (FSH) causes follicles to mature in the ovaries with one becoming dominant. Around day 14, luteinizing hormone (LH) surges causing ovulation of the dominant follicle. The remaining follicle cells form the corpus luteum which secretes progesterone to prepare the endometrium for potential implantation. If implantation does not occur, progesterone and estrogen levels fall, causing menstruation and the start of a new cycle.

1. Dr. Anshika jain

2. What is the mean duration of the MC?
Mean 28 days (only 15% of ♀)
Range 21-35
What is the average duration of menses?
3-8 days
What is the normal estimated blood loss?
Approximately 30 ml
When does ovulation occur?
Usually day 14
36 hrs after the onset of mid-cycle LH surge

3. What regulate the phases of the MC & ovulation?
Interaction between hypothalamus, pituitary & ovaries
What is the mean age of menarche & menopause?
Menarche 12.7
Menopause 51.4

5.  The hypothalamus secretes GnRH in a pulsatile fashion
 GnRH activity is first evident at puberty
 Follicular phase GnRH pulses occur hourly
 Luteal phase GnRH pulses occur every 90 minutes
 Loss of pulsatility down regulation of pituitary receptors
  secretion of gonadotropins
 Release of GnRH is modulated by –ve feedback by:
steroids
gonadotropins
 Release of GnRH is modulated by external neural signals

6. Ovulation divides the Mens. Cycle into
two phases:
1. Follicular/ pre-ovulatory ovarian phase/ Proliferative
phase
variable.
2. Secretory/ postovulatory endometrial phase.
constant.

7.  At 20 weeks of gestational age- 6-7 million.
 At birth- 2 million
 At puberty- 4 lakh.
 400 ovulate in entire reproductive life.

8. -Begins with menses on day 1 of the menstrual
cycle
& ends with ovulation
 RECRUITMENT
FSH  maturation of a cohort of ovarian
follicles
 only one reaches maturity

9. A- Primordial follicle
B- Preantral follicle
C- Antral follicle
D- Preovulatory follicle

10. Primordial follicle in the cortical stroma. A layer of flattened follicular
epithelial cells surrounds the oocyte with its large nucleus and prominent
nucleolus. The ooplasm is not stained

11.  The granulosa cells become cuboidal and increase
in number to form a pseudostratified layer.
 The decline in luteal phase estrogen, progesterone,
and inhibin-A production by the now-fading
corpus luteum from the previous cycle
 The increase in FSH that stimulates this follicular
growth.
 Hormone-mediated effects can be transmitted
throughout the follicle.
 Oocyte begins secretion of an acellular coat known
as the zona pellucida.

12.  The stroma differentiates into the theca interna, which
is adjacent to the basal lamina, and the theca externa,
which abuts the surrounding stroma
 Oocyte enlarges and is surrounded by a membrane,
the zona pellucida
 Granulosa cells -> estrogen

13. Ovary—Secondary Follicle or Preantral Follicle
1 Follicular epithelium
2 Zona pellucida
3 Basal membrane
4 Theca folliculi

14. Ovary—Secondary Follicle or Preantral Follicle
1 Beginnings of a follicular antrum
2 Theca folliculi interna
3 Theca folliculi externa
4 Cortical stroma
5 Primordial follicle

15.  Specific receptors for FSH are not detected on
granulosa cells until the preantral stage, needed
for androgen aromatase

16. MATURATION OF THE FOLLICLE (FOLLICULOGENESIS)
 FSH  primordial follicle
(oocyte arrested in the diplotene stage of the 1st meiotic
division surrounded by a single layer of granulosa cells)
 Containing the ovum surrounded by a single layer of
flattened granulosa cells and are present at birth.
 Growth not dependent on gonadotropins.
  primary follicle
(oocyte surrounded by a single layer of granulosa cells
basement membrane & theca cells).

19.  secondary follicle or preantral follicle
(oocyte surrounded by zona pellucida , several layers of
granulosa cells & theca cells).
Is hormone-independent and involves growth and
differentiation of primordial follicles to form primary
follicles.
 The stimulus is not known at present.

20.  During this phase the ovum undergoes
 Its major growth,
 The follicular cells acquire receptors for FSH and
estrogen in the granulosa cells and receptors for LH
appear on thecal cells.
 Each cycle, 15-20 follicles are stimulated, granulosa
cells become taller, start to proliferate and secrete
E2 .

21. SELECTION
 Selection of the dominant follicle occurs day 5-7
 It depends on
- the intrinsic capacity of the follicle to synthesize
estrogen.
- high estrogen/androge ratio in the follicular fluid
 As the follicle mature   estrogen  FSH
“-ve feed back on the pituitary”  the follicle
with the highest No. of FSH receptors will
continue to survive.
 The other follicles “that were recruited” will
become atretic.

22. Secondary follicle accumulate fluid in a cavity
“antrum”.
Oocyte is in eccentric position.
Surrounded by granulosa cells “cumulous
oophorus”.

25.  Follicular fluid begins to collect between the granulosa
cells→ antrum.
 Rapid increase in follicular size
 The granulosa cells surrounding the oocyte are now
designated the cumulus oophorus

26.  1 Antrum folliculi
 2 Cumulus oophorus with oocyte
 3 Theca folliculi

28.  FSH ACTIONS:
-recruitement
-mitogenic effect   No. of granulosa
cells
- FSH receptor
-stimulates aromatase activity 
conversion of
androgens  estrogens “estrone & estradiol”
-  LH receptors

29.  ESTROGEN
Acts synergistically with FSH to
- induce LH receptors
- induce FSH receptors in
granulosa
& theca cells
 LH  theca cells  uptake of cholesterol &
LDL 
androstenedione & testosterone.

30.  Inhibin: Inhibitor of
FSH secretion.
 Activin: Stimulates
FSH release
 Follistatin : binding
activin: Suppresses
FSH activity

31. 2 Forms of Inhibin:
 Inhibin A: Alpha-BetaA ( Corpus Luteum-Luteal Phase)
 Inhibin B: Alpha-BetaB ( Granulosa Cells-Follicular Phase )
Inhibin: block the synthesis and secretion of FSH, reduce
the number of GnRH receptors present, promotes
intracellular degradation of gonadotropins.
FSH - Inhibin — a reciprocal relationship
Inhibin B: rises slowly but steadily, in a pulsatile fashion
(60–70 min periodicity) reaching peak levels in the early
and midfollicular phases, a nadir in the midluteal phase.
Inhibin A: suppression of FSH to nadir levels during the
luteal phase

32.  Activin :
 Prior to ovulation: supress Progesteron production
 Stimulate FSH release and GnRH receptor number.
 Circulating levels of activin increase in the late
luteal phase to peak at menses

33.  Follistatin playing a
role by inhibiting
activin and enhancing
inhibin activity.

34.  The successful conversion to an estrogen dominant
follicle marks the “selection” of a follicle destined
to ovulate -> One Single Follicle Succeed ->
Dominant Follicle -> Estrogen
 estrogen - FSH interaction (+ for maturing follicle)
 estrogen - pitutary interaction (- feedback)
-> FSH ↓
Other cells entered Apoptosis -> TNF -> inhibit FSH
stimulation , estradiol secretion

35.  Estrogens - LH (+ feedback) -> Luteinization of
the granulosa cells -> Progesterone &
Prostaglandin -> Initiation of ovulation
 Plasminogen -> Proteolytic enzymes, plasmin

36.  The dominant follicle protrudes from the ovarian cortex
 Gentle release of the oocyte surrounded by the cumulus
granulosa cells
 Mechanism of follicular rupture
1- Follicular pressure
Changes in composition of the antral fluid   colloid
osmotic pressure
2-Enzymatic rupture of the follicular wall
LH & FSH  granulosa cells  production of
plasminogen activator
  plasmin   fibrinolytic activity  breake down of F.
wall
LH   prostglandin E   plasminogen activator
  PG F2α   lysosomes under follicular wall

37.  Inhibin, Activin and follistatin, insulinlike growth
factor (ILGF)-1, epidermal growth factor
(EGF)/transforming growth factor (TGF)-α, TGF-β1, β-
fibroblast growth factor (FGF), interleukin-1, tissue
necrosis factor-α, OMI, and renin–angiotensin

38. Ovary—Graafian Follicle
Human follicles reach a
diameter of 20–25mm
1 Antrum folliculi
2 Cumulus oophorus
3 Granulosa epithelial cells
4 Theca folliculi
5 Radial corona cells

39.  Oocyte-cumulus is released from
the follicle
 Toward the end of the follicular
phase, estradiol levels increase
dramatically
 Estradiol - Pituitary (+ Feedback)
 Estradiol concentrations of 200
pg/mL for 50 hours →initiate a
gonadotropin surge
 The mean duration of the LH surge
is 48 hours

40.  A threshold of LH concentration must be maintained
for at least 14 to 27 hours in order for full maturation of
the oocyte to occur.
 Usually the LH surge lasts 48 to 50 hours
 Ovulation will occur in the single mature, Graafian
follicle 10 to 12 hours after the LH peak or 34 to 36 hours
after the initial rise in midcycle LH.

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

43. Gn surge -> Plasminogen activity ↑
Plasmin and collagenase-> follicular
wall thinning
Prostaglandin-> Ovary muscle
contraction
Extrusion of the oocyte only lasts a few
minutes

44.  The remaining -> corpus
luteum
 granulosa / theca cells
proliferate +
hypertrophy ->
granulosa-lutein cells /
smaller theca-lutein cells
 Basement membrane
degenerates + vascularize
-> Capillary invasion
 Progesterone Dominant ->
40 mg of progesterone per
day
 Inhibin A -> low FSH level

45. 1 Granulosa lutein cells
2 Theca lutein cells
3 Connective tissue of the theca folliculi

46. LASTS 14 days
FORMATION OF THE CORPUS LUTEUM
 After ovulation the point of rupture in the follicular wall
seals
 Vascular capillaries cross the basement membrane & grow
into the granulosa cells  availability of LDL-cholestrole
LH  LDL binding to receptors
 3α OH steroid dehydrogenase activity
 progestrone

47.  Marked  in progestrone secretion
 Progestrone actions:
-suppress follicular maturation on the
ipsilateral ovary
-thermogenic activity  basal body temp
-endometrial maturation
 Progestrone peak 8 days after ovulation (D22 MC)
 Corpus luteum is sustained by LH
 It looses its sensitivity to gonadotropins  luteolysis 
estrogen & progestrone level  desquamation of the
endometrium “menses”

48.  estrogen & progesterone   FSH &LH
 The new cycle starts with the beginning of menses
 If pregnancy occurs  hCG secretion  maintain the
corpus luteum .

49.  Luteal regression
 Blood supply diminishes
 E & P secretion drop
 Luteal cells apoptosis -> fibrotic -> corpus albicans

50.  Estradiol, progesterone, inhibin -> nadir
 E & P decrease -> increasing GnRH pusatile
 Inhibin A decrease + increasing GnRH pulsatile ->
FSH > LH

52.  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.

53.  Decidua functionalis
-intermediate zone (stratum spongiosum)
-superficial compact zone (stratum compactum).
 Decidua basalis is the deepest region of the endometrium

55.  The glands :
 narrow and tubular, lined by low columnar epithelium
cells.
 Mitoses
 Pseudostratification
 A continuous epithelial lining facing the endometrial
cavity is formed.

56. THE PROLIFERATIVE PHASE

57.  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.

58.  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 cells

59.  Early proliferative phase, the endometrium is
relatively thin (1–2 mm).
 Initially straight, narrow, and short endometrial
glands → longer structures.
 These proliferating glands have multiple mitotic
cells
 Low columnar pattern → pseudostratified pattern
before ovulation.
 Estrogen  mitotic activity in the glands & stroma

 endometrial thickness from 2 to 8 mm
(from basalis to opposed basalis layer)

60.  Proliferative phase:
straight to slightly
coiled, tubular
glands are lined by
pseudostratified
columnar epithelium
with scattered
mitoses.

61. THE SECRETORY PHASE

62. Early secretory phase:
 48-72 hours after
ovulation:
Progesteron↑
 coiled glands lined by
simple columnar
epithelium
 glycogen containing
vacuoles
 Apocrine secretion
 Stroma edema

63. Progestrone - Mitotic activity is severely restricted
-Endometrial glands produce then
secrete
glycogen rich vacules
-Stromal edema
-Stromal cells enlargement
-Spiral arterioles develop, lengthen &
coil

64.  Late secretory phase:
 serrated, dilated glands
with intraluminal
secretion are lined by short
columnar cells.
 2 days before menses:
PMN
infilitration→endometrial
stroma collapse

65.  D-17: glycogen accumulates in basal portion of
glandular portion c/a subnuclear vacuolisation.- 1st
sign of ovulation i.e. histological evident.
 D-18- vacuoles move to apical portion.
 D19- these cells begin to secrete glycoprotein and
mucopolysaccharide.
 D-21-24- stroma become edematous.
 D23-28- predecidual cells surrounding spiral
arterioles.

66.  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)

67.  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

68. IMPLANTATION PHASE

69.  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.

70.  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

71. ENDOMETRIAL BREAKDOWN

72.  Decidua functionalis
breakdown→menses
 Sex steroids withdrawal:
spiral artery vascular
spasm →endometrial
ischemia.
 Lysosomes breakdown
→proteolytic enzymes
→promote local tissue
destruction.
 Prostaglandin F2α →
potent vasoconstrictor→
arteriolar vasospasm and
endometrial ischemia.
PGF2α also produces
myometrial contractions

73.  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.

74.  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.

75.  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.

76.  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

77.  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

78.  Progesterone withdrawal from endometrial cells
induces matrix metalloproteinase secretion.
 In a nonpregnant cycle, metalloproteinase expression
is suppressed after menses by increasing estrogen
levels.

79.  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.

80.  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

81.  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

82.  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.

83.  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.

84.  Within 13 hours, the endometrial height shrinks from
4 mm to 1.25 mm.
 Menstrual flow stops as a result of the combined
effects of
 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.