Just a presentation covering the physiology of menstruation

1. +
Physiology Of
Menstruation
Dr Anusha Rao P
PGY2 (OBG)

2. +
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: 24-38 days
 Regularity: +/- 2-20 days
 Duration: 4-8 days
 Volume: 5-80 mL

3. +

4. +HORMONES FOLLICULAR
PHASE
OVULATION LUTEAL PHASE
DAILY
PRODUCTION
(ug)
OESTRADIOL
PROGESTERONE
50
2 - 3
150-300 100
20 -30
SERUM VALUES
OESTRADIOL
(pg/ml)
PROGESTERONE
(ng/ml)
FSH (mIU/ml)
LH (mIU/ml)
50
<1
10
5
300- 600
15- 20
60
150-200
>5
10
5
DAILY
EXCRETION
TOTAL
OESTROGEN (ug)
PREGNANEDIOL
(mg)
10-25
<1
35- 100 25-75
3-6

5. +

6. +
 Menstrual cycle can be explained in two cycles which occur
concurrently
• 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

7. +
THE OVARIAN
CYCLE

8. + Follicular
phase

9. +

10. +
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.

11. +
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.

12. +
 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

13. +
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

14. +
The 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.

15. +
 The granulosa cells of the preantral follicle synthesizes all 3 classes of
steroids
 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.

16. +
FSH both
 initiates steroidogenesis (estrogen production) in granulosa
cells and
 stimulates granulosa cell growth and proliferation

17. +

18. +
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
cumulus oophorus

19. +
P45OC17
P450arom

20. +
The Two-Cell,
Two-Gonadotropin System
 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
 LH stimulates thecal cells to produce androgens that can then
be converted, through FSH-induced aromatization, to
estrogens in the granulosa cells.

21. +
 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

22. +
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.

23. +
 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.

24. +
 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.

25. +

26. +
 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.

27. +
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.

28. +
 Inhibin
 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
gonadotropins.

29. +
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
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.

30. +
 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

31. +
 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.

32. +
 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.
- for atresia of lesser follicles and for libido
enhancement

33. +
Ovulation

34. +
 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

35. +
LH, FSH, Progesterone, growth factors
Plasminogen activator synthesis (granulosa &theca cells)
Plasminogen Plasmin
Collagenase
Disrupts follicular wall

36. +

37. +
 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)

38. +
LUTEAL
PHASE

39. +
 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.

40. +
 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.

41. +
 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

42. +
 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,

43. +
 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.

44. +
 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.

45. +

46. +
The Luteal-
Follicular
Transition

47. +
 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.

48. +

49. +HORMONES FOLLICULAR
PHASE
OVULATION LUTEAL PHASE
DAILY
PRODUCTION
(ug)
OESTRADIOL
PROGESTERONE
50
2 - 3
150-300 100
20 -30
SERUM VALUES
OESTRADIOL
(pg/ml)
PROGESTERONE
(ng/ml)
FSH (mIU/ml)
LH (mIU/ml)
50
<1
10
5
300- 600
15- 20
60
150-200
>5
10
5
DAILY
EXCRETION
TOTAL
OESTROGEN (ug)
PREGNANEDIOL
(mg)
10-25
<1
35- 100 25-75
3-6

50. +
 From the midluteal peak to menses,
 there is a 4.5-fold increase in LH pulse frequency
 FSH pulse frequency increases 3.5-fold
 The increase in FSH is, as noted, greater than that of LH.

51. +
UTERINE CYCLE

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. +

54. +
The Proliferative Phase
 The glands :
 narrow and tubular, lined by low columnar epithelium cells.
 Mitoses
 Pseudostratification
 A continuous epithelial lining facing the endometrial cavity is
formed.

55. + THE
PROLIFERATIVE
PHASE

56. +
 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.

57. +
 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

58. + THE
SECRETOR
Y PHASE

59. +
 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)

60. +
 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

61. +
IMPLANTATION
PHASE

62. +
 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.

63. +
 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

64. +
ENDOMETRIAL
BREAKDOWN

65. +
 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.

66. +
 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.

67. +
 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.

68. +
 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

69. +

70. +
 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

71. +
 Progesterone withdrawal from endometrial cells induces matrix
metalloproteinase secretion.
 In a nonpregnant cycle, metalloproteinase expression is
suppressed after menses by increasing estrogen levels.

72. +

73. +
 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.

74. +
 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

75. +
 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

76. +
 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.

77. +
 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.

78. +
 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.

79. +
THANK YOU