The document summarizes the physiology of menstruation. It describes the hypothalamic-pituitary-ovarian axis that regulates the menstrual cycle. The cycle consists of two concurrent cycles - the ovarian cycle and the uterine cycle. The ovarian cycle includes the follicular phase where a follicle is selected for ovulation, and the luteal phase where the corpus luteum forms. The uterine cycle includes the proliferative phase where the endometrium thickens in response to estrogen, and the secretory phase where it is remodeled by progesterone in preparation for implantation. If implantation does not occur, hormone levels drop and the endometrium breaks down and is shed, resulting in menstruation.

1. +
Physiology Of
Menstruation
av sharma

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: 21-35 days
 Duration: 3-5 days
 Volume: 50-200 mL

3. + The hypothalamic–pituitary–ovarian axis (also HPO axis) refers
to the effects of the hypothalamus, pituitary gland, and ovaries as
if these individual endocrine glands were a single entity as a
whole.

4. + Feedback mechanisms in hpo axis

5. +
 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

6. +

7. +
THE OVARIAN
CYCLE

8. +

9. + Follicular
phase

10. +

11. +
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.

12. +
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.

13. +
 The initial recruitment and growth of the primordial follicles is gonadotropin
independent
 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

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

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

17. +
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

18. +
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.

19. +
P45OC17
P450arom

20. +

21. +
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.

22. +
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 veins
 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.

23. +
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.

24. +
 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

25. +
Ovulation

26. +
 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

27. +
LH, FSH, Progesterone, growth factors
Plasminogen activator synthesis (granulosa &theca cells)
Plasminogen Plasmin
Collagenase
Disrupts follicular wall

28. +

29. +
LUTEAL
PHASE

30. +
 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.

31. +
The leukocytes in the corpus luteum secrete
cytolytic enzymes, prostaglandins, and
growth factors involved in angiogenesis,
steroidogenesis, and luteolysis.

32. +
Angiogenesis
Vascularization of the granulosa layer is
essential to allow LDL-cholesterol to reach
the luteal cells to provide sufficient substrate
for progesterone.

33. +
 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,

34. +
 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.

35. +
UTERINE CYCLE

36. +
 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.

37. +

38. + THE
PROLIFERATIVE
PHASE

39. +
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.

40. +
 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.

41. +
 The endometrium grows from approximately 0.5 mm to 3.5 to
5.0 mm in height
 An important feature of this estrogen-dominant phase of
endometrial growth is the increase in ciliated and microvillous
cells

42. + THE
SECRETOR
Y PHASE

43. +
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

44. +
 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
 The peak secretory level is reached 7 days after the midcycle gonadotropin
surge

45. +
IMPLANTATION
PHASE

46. +
 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 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 layer.

47. +
 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

48. +
ENDOMETRIAL
BREAKDOWN

49. +
 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 shrinking of the tissue height and spiral arteriole vasomotor
responses.

50. +
 The following vascular sequence occurs
 With shrinkage of height, blood flow within the spiral vessels
diminishes, venous drainage is decreased, and vasodilation occurs.
 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.

51. +

52. +
 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; etc

53. +
 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

54. +
 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.

55. +
 A natural cleavage point exists between basalis and
spongiosum, and, once breached, spongiosum collapses.
 The process is initiated in the fundus and extends throughout
the uterus.

56. +
 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,
 Vascular stasis,
 Estrogen-induced healing
 In contrast to postpartum bleeding, myometrial contractions are
not important for control of menstrual bleeding.

57. +
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