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Physiology Of
Menstruation
av sharma
+
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
+ 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.
+ Feedback mechanisms in hpo axis
+
 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
+
+
THE OVARIAN
CYCLE
+
+ Follicular
phase
+
+
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
 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
+
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.
+
The granulosa cells of the preantral follicle
synthesizes all 3 classes of steroids
Estrogens are produced more than
androgens or progestins
+
FSH both
initiates steroidogenesis (estrogen
production) in granulosa cells and
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
cumulus oophorus
+
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.
+
P45OC17
P450arom
+
+
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.
+
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.
+
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.
+
 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
+
Ovulation
+
 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
+
LH, FSH, Progesterone, growth factors
Plasminogen activator synthesis (granulosa &theca cells)
Plasminogen Plasmin
Collagenase
Disrupts follicular wall
+
+
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.
+
The leukocytes in the corpus luteum secrete
cytolytic enzymes, prostaglandins, and
growth factors involved in angiogenesis,
steroidogenesis, and luteolysis.
+
Angiogenesis
Vascularization of the granulosa layer is
essential to allow LDL-cholesterol to reach
the luteal cells to provide sufficient substrate
for progesterone.
+
 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.
+
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.
+
+ THE
PROLIFERATIVE
PHASE
+
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.
+
 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
 An important feature of this estrogen-dominant phase of
endometrial growth is the increase in ciliated and microvillous
cells
+ THE
SECRETOR
Y 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
+
 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
+
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 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.
+
 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
+
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 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 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.
+
+
 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
+
 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
+
 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.
+
 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.
+
 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.
+
THANK YOU
Physiology of menstruation by av sharma

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Physiology of menstruation by 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. +
  • 8. +
  • 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.
  • 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
  • 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. +
  • 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.
  • 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. +
  • 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
  • 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
  • 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
  • 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.