Menstruation & Menstruation & ovulationovulation

PHYSIOLOGY OF PHYSIOLOGY OF MENSTRUAL CYCLEMENSTRUAL CYCLE

The normal menstrual cycle is The normal menstrual cycle is divided into:divided into:

1. The ovarian cycle.1. The ovarian cycle. 2. The uterine cycle.2. The uterine cycle.

THE OVARIAN CYCLETHE OVARIAN CYCLE

The changes that occur in the ovary The changes that occur in the ovary during each cycle can be divided into during each cycle can be divided into three stages: (1) The follicular phase three stages: (1) The follicular phase (day 1 to 13), (2) Ovulatory phase (day 1 to 13), (2) Ovulatory phase (day 13 to 15) and (3) The luteal (day 13 to 15) and (3) The luteal phase (day 15 to 28).phase (day 15 to 28).

1.1. The Follicular phase:The Follicular phase: During the follicular phase, certain During the follicular phase, certain

number of follicles start to grow and some of number of follicles start to grow and some of them will pass from the stage of primordial them will pass from the stage of primordial follicle to the stage of preantral follicle, and follicle to the stage of preantral follicle, and usually few of them can pass to the antral usually few of them can pass to the antral follicle stage of which one only succeeds to follicle stage of which one only succeeds to continue through the pre-ovulatory follicle continue through the pre-ovulatory follicle stage. In each of these stages, there are many stage. In each of these stages, there are many cellular, histological, hormonal and functional cellular, histological, hormonal and functional changes that occur with interaction between changes that occur with interaction between the gonadotropins and the ovarian steroid the gonadotropins and the ovarian steroid hormones.hormones.

A.A. The primordial follicle:The primordial follicle: During the intrauterine life, the ovarian During the intrauterine life, the ovarian

differentiation starts in-between the 6th and the differentiation starts in-between the 6th and the 8th week by proliferation and multiplication of 8th week by proliferation and multiplication of the germ cells to reach a huge number (6-7 the germ cells to reach a huge number (6-7 millions) around the 20th week. The germ cells millions) around the 20th week. The germ cells stop mitotic division and start meiosis under the stop mitotic division and start meiosis under the effect of secretions of the mesonephric tubules-effect of secretions of the mesonephric tubules-derived cells "Rete cells" called meiosis derived cells "Rete cells" called meiosis inducing substance. Passing through the early inducing substance. Passing through the early stages of meiosis, the oocytes will be arrested stages of meiosis, the oocytes will be arrested at the prophase of meiosis and become at the prophase of meiosis and become surrounded by a layer of perivascular cells that surrounded by a layer of perivascular cells that are both mesenchymal and epithelial in origin are both mesenchymal and epithelial in origin to form the primordial follicles. Failure of to form the primordial follicles. Failure of achieving this coating by the granulosa cells achieving this coating by the granulosa cells would lead germ cell to complete meiosis and would lead germ cell to complete meiosis and die with marked reduction of the germ cell die with marked reduction of the germ cell population. This process requires the presence population. This process requires the presence of two X chromosomes and so, in 45XO of two X chromosomes and so, in 45XO chromosomal pattern of Turner's syndrome, chromosomal pattern of Turner's syndrome, gonadal dysgenesis occurs.gonadal dysgenesis occurs.

The primordial follicle is composed of oocyte arrested The primordial follicle is composed of oocyte arrested in the diplotene stage of meiotic prophase, in the diplotene stage of meiotic prophase, surrounded by a single layer of pregranulosa cells surrounded by a single layer of pregranulosa cells (germinal epithelial) resting on a basement (germinal epithelial) resting on a basement membrane separating it from an outer less organized membrane separating it from an outer less organized matrix of pretheca cells (mesenchymal cells). The matrix of pretheca cells (mesenchymal cells). The rest of mesenchymal cells not utilized in primordial rest of mesenchymal cells not utilized in primordial follicle formation is noted in the interstices between follicle formation is noted in the interstices between follicles, forming the primitive ovarian stroma. follicles, forming the primitive ovarian stroma.

The process of follicular maturation is The process of follicular maturation is described as a described as a ContinuumContinuum. It means that (The initial . It means that (The initial stages of follicular growth occur during all stages of follicular growth occur during all physiological conditions without any external physiological conditions without any external stimulation). Each follicle seems to have a genetic stimulation). Each follicle seems to have a genetic code for the timing at which it may resume growth. code for the timing at which it may resume growth. The number of follicles that resumes growth at any The number of follicles that resumes growth at any point of time is dependent on the size of the residual point of time is dependent on the size of the residual pool of follicles in both ovaries and if the residual pool of follicles in both ovaries and if the residual pool is changed dramatically at any time, the pool is changed dramatically at any time, the remaining follicles will rescheduled their readiness to remaining follicles will rescheduled their readiness to resume growth according to the new situation.resume growth according to the new situation.

The first visible sign that the follicle resumes growth is The first visible sign that the follicle resumes growth is that the granulosa cells become cubical rather than that the granulosa cells become cubical rather than squamous in shape. Mitosis appears in the granulosa squamous in shape. Mitosis appears in the granulosa cells, the oocyte expands and starts to secrete the zona cells, the oocyte expands and starts to secrete the zona pellucida (ZP). The overall diameter of the primordial pellucida (ZP). The overall diameter of the primordial follicle is about 50follicle is about 50 and the oocyte is about 20 and the oocyte is about 20 . Gap . Gap junctions develop between surrounding granulosa cells junctions develop between surrounding granulosa cells and the oocyte to establish a metabolic and electric and the oocyte to establish a metabolic and electric linkage that will persist at ovulation. Not all granulosa linkage that will persist at ovulation. Not all granulosa cells are receptor +ve, so activation signals, protein cells are receptor +ve, so activation signals, protein kinase and cyclic AMP can pass from receptor +ve kinase and cyclic AMP can pass from receptor +ve granulosa cells to receptor -ve cells.granulosa cells to receptor -ve cells.

Once the primordial follicle resumes growth, the Once the primordial follicle resumes growth, the process is irreversible, so if the situation is favorable, it process is irreversible, so if the situation is favorable, it would passes to the next stage, otherwise, atresia is the would passes to the next stage, otherwise, atresia is the definitive fate. So the number of follicles in the ovaries is definitive fate. So the number of follicles in the ovaries is reduced dramatically as time passes. The general pattern reduced dramatically as time passes. The general pattern is initial growth followed by atresia which is interrupted at is initial growth followed by atresia which is interrupted at the beginning of the cycle during menses or even during the beginning of the cycle during menses or even during the last very few days of the previous cycle where a the last very few days of the previous cycle where a group of emerging follicles is exposed, responds to the group of emerging follicles is exposed, responds to the rising peptide hormones stimulation ( withdrawal of the -rising peptide hormones stimulation ( withdrawal of the -ve feedback as the CL degenerates) and is propelled to ve feedback as the CL degenerates) and is propelled to further growth.further growth.

The maximum number ( 6-7 millions ) is present The maximum number ( 6-7 millions ) is present at the 20th week of intrauterine life, of which 2 at the 20th week of intrauterine life, of which 2 millions are present at birth. No similar rate of millions are present at birth. No similar rate of depletion of the germ cell mass is seen again, and depletion of the germ cell mass is seen again, and there is evidence that the major mechanism for there is evidence that the major mechanism for this loss is by elimination through the surface of this loss is by elimination through the surface of the ovary into the peritoneal cavity. At the onset the ovary into the peritoneal cavity. At the onset of puberty, the germ cell mass has been reduced of puberty, the germ cell mass has been reduced to 300,000. During the next 30-45 years of to 300,000. During the next 30-45 years of reproductive life, these units will be depleted reproductive life, these units will be depleted further to a point at menopause where follicles further to a point at menopause where follicles are almost completely depleted. As 300-500 are almost completely depleted. As 300-500 follicles would grow enough to reach the ovulation follicles would grow enough to reach the ovulation phase, for each of them close to 1,000 will pursue phase, for each of them close to 1,000 will pursue abortive growth periods of variable length.abortive growth periods of variable length.

B.B. The Preantral Follicle:The Preantral Follicle: Once growth is initiated, the follicle passes to the Once growth is initiated, the follicle passes to the

preantral stage where the oocyte enlarges to reach a size preantral stage where the oocyte enlarges to reach a size of 80of 80 ( same size till ovulation, limited by the ZP ). The ( same size till ovulation, limited by the ZP ). The granulosa cells undergo multilayer proliferation and the granulosa cells undergo multilayer proliferation and the theca cells begins to organize from the surrounding theca cells begins to organize from the surrounding stroma with the development of its own newly formed stroma with the development of its own newly formed blood vessels. The overall diameter of the follicle at this blood vessels. The overall diameter of the follicle at this stage is about 200stage is about 200..

The growth in this stage is dependent on the The growth in this stage is dependent on the gonadotropin stimulation. LH acts mainly on the theca gonadotropin stimulation. LH acts mainly on the theca cells to start steroidogenesis and the production of cells to start steroidogenesis and the production of androgens mainly testosterone and androstenedione. androgens mainly testosterone and androstenedione. These androgens may pass directly to the blood stream, These androgens may pass directly to the blood stream, but also some of it will back-diffuse toward the granulosa but also some of it will back-diffuse toward the granulosa cell layer where it is aromatized by the granulosa cells cell layer where it is aromatized by the granulosa cells under the effect of FSH. FSH not only stimulates the under the effect of FSH. FSH not only stimulates the conversion of androgens to estrogen but also propels conversion of androgens to estrogen but also propels follicles to the antral stage by stimulating granulosa cell follicles to the antral stage by stimulating granulosa cell mitosis. Together, FSH and estrogen increase the FSH mitosis. Together, FSH and estrogen increase the FSH receptors content of the follicle with a resulting receptors content of the follicle with a resulting snowballing effect on follicle growth and differentiation.snowballing effect on follicle growth and differentiation.

Androgen plays a delicate role to determine Androgen plays a delicate role to determine the fate of the follicle. The presence of the fate of the follicle. The presence of moderate amounts of androgen in the moderate amounts of androgen in the follicle not only acts as a substrate but also follicle not only acts as a substrate but also via androgen specific receptor- stimulates via androgen specific receptor- stimulates its aromatization to estrogen while its aromatization to estrogen while excessive androgen would act as anti-excessive androgen would act as anti-estrogen to inhibit aromatization leading to estrogen to inhibit aromatization leading to androgen accumulation converted to 5androgen accumulation converted to 5--reduced form which can not be converted to reduced form which can not be converted to estrogen , so, the follicle becomes estrogen , so, the follicle becomes androgenic and ultimately atretic.androgenic and ultimately atretic.

C.C. Antral Follicle:Antral Follicle: As the follicle continues its growth under the As the follicle continues its growth under the

combined effect of FSH and estrogen, follicular combined effect of FSH and estrogen, follicular fluid accumulates in the intercellular spaces to fluid accumulates in the intercellular spaces to form Call-Exner bodies and coalescing together to form Call-Exner bodies and coalescing together to form the characteristic follicular cavity "The form the characteristic follicular cavity "The Antrum" . The antrum provides a specific hormonal Antrum" . The antrum provides a specific hormonal environment for the oocyte and the avascular environment for the oocyte and the avascular granulosa cell layer which is different from that of granulosa cell layer which is different from that of the serum and the other follicles. The oocyte now the serum and the other follicles. The oocyte now bulges in the antrum being surrounded by few bulges in the antrum being surrounded by few layers of granulosa cell called cumulus oophorus layers of granulosa cell called cumulus oophorus which attaches the oocyte to the rest of the which attaches the oocyte to the rest of the granulosa cell. The theca cell layer is differentiated granulosa cell. The theca cell layer is differentiated to well organized highly vascular theca interna and to well organized highly vascular theca interna and less organized less vascular theca externa.less organized less vascular theca externa.

The antral follicle is characterized by the highest level of The antral follicle is characterized by the highest level of granulosa cell proliferation, highest rate of FSH activity granulosa cell proliferation, highest rate of FSH activity through huge number of FSH receptors, and so the greatest through huge number of FSH receptors, and so the greatest ability to convert androgen to estrogen making the antral ability to convert androgen to estrogen making the antral follicle an estrogen-dominant follicle with accumulation of follicle an estrogen-dominant follicle with accumulation of FSH and estrogen in the antrum. This is accompanied by a FSH and estrogen in the antrum. This is accompanied by a high degree of theca cell layer vascularization which allows high degree of theca cell layer vascularization which allows a preferential delivery of FSH and LH to this follicle. The a preferential delivery of FSH and LH to this follicle. The successful conversion to an estrogen-dominant follicle successful conversion to an estrogen-dominant follicle marks the selection of the follicle destined to ovulate "the marks the selection of the follicle destined to ovulate "the dominant follicle", a process by which, except in rare dominant follicle", a process by which, except in rare exception, only one follicle ovulates each cycle. The natural exception, only one follicle ovulates each cycle. The natural selection of the dominant follicle is evident by day 7 of the selection of the dominant follicle is evident by day 7 of the cycle, although the process of selection started at an earlier cycle, although the process of selection started at an earlier stage when one of the primordial follicles has good stage when one of the primordial follicles has good synchronization between its timed resumption of growth synchronization between its timed resumption of growth and the elevated level of FSH seen during the last few days and the elevated level of FSH seen during the last few days of the previous cycle.of the previous cycle.

This emerging dominant follicle produces about 95% This emerging dominant follicle produces about 95% of the entire ovarian secretion. Within the antral of the entire ovarian secretion. Within the antral follicle, estrogen interacts with FSH to help follicle, estrogen interacts with FSH to help maturation of the dominant follicle, while estrogen maturation of the dominant follicle, while estrogen released in the circulation has a -ve feedback effect released in the circulation has a -ve feedback effect on the production and release of FSH from the on the production and release of FSH from the anterior pituitary leading to a gradual drop in anterior pituitary leading to a gradual drop in circulating FSH level. The drop in FSH level would circulating FSH level. The drop in FSH level would reduce aromatase activity in less mature, less reduce aromatase activity in less mature, less vascularized follicles and reduce granulosa cell vascularized follicles and reduce granulosa cell proliferation and activity promoting accumulation of proliferation and activity promoting accumulation of androgen thereby inducing irreversible atretic androgen thereby inducing irreversible atretic changes. The dominant follicle is immune from the changes. The dominant follicle is immune from the drop in FSH as it has its own reservoir of FSH in the drop in FSH as it has its own reservoir of FSH in the antrum with the highest granulosa cell mass and the antrum with the highest granulosa cell mass and the highest degree of FSH receptors. So a wave of highest degree of FSH receptors. So a wave of atresia among smaller follicles is seen in parallel to atresia among smaller follicles is seen in parallel to the rise of circulating estrogen produced from the the rise of circulating estrogen produced from the dominant follicle.dominant follicle.

D.D. Preovulatory Follicle:Preovulatory Follicle: At this stage the follicle attains a big size, it At this stage the follicle attains a big size, it

measures 20 mm or more. The granulosa cells measures 20 mm or more. The granulosa cells enlarge and attain lipid inclusion, while the theca enlarge and attain lipid inclusion, while the theca cells are highly vascularized with even more cells are highly vascularized with even more luteinization.luteinization.

The oocyte resumes the nuclear component The oocyte resumes the nuclear component of meiosis I. It passes from the late stages of the of meiosis I. It passes from the late stages of the prophase to the metaphase, anaphase and finally to prophase to the metaphase, anaphase and finally to the telephase of meiosis I. It is at this stage when the telephase of meiosis I. It is at this stage when the haploid number of chromosomes is produced as the haploid number of chromosomes is produced as one pair of the chromosomes together with a little one pair of the chromosomes together with a little cytoplasm forms the first polar body that lies free cytoplasm forms the first polar body that lies free inside the zona pellucida, while the second pair with inside the zona pellucida, while the second pair with the rest of the cytoplasm forms the secondary the rest of the cytoplasm forms the secondary oocyte. Meiosis I is completed during this stage and oocyte. Meiosis I is completed during this stage and the secondary oocyte enter meiosis II immediately the secondary oocyte enter meiosis II immediately before ovulation. Meiosis II is only completed at the before ovulation. Meiosis II is only completed at the entry of the sperm at the time of fertilization.entry of the sperm at the time of fertilization.

It is at this stage when the hypothalamic-pituitary ovarian It is at this stage when the hypothalamic-pituitary ovarian interaction is at the most critical point with great synchrony interaction is at the most critical point with great synchrony and harmony:and harmony:

Estrogen, mainly from the dominant follicle, reaches a high Estrogen, mainly from the dominant follicle, reaches a high level and it should reaches a level of 200 pg/ml or more in the level and it should reaches a level of 200 pg/ml or more in the plasma to be maintained for at least 50 hours in order to plasma to be maintained for at least 50 hours in order to produce the positive feedback on the pituitary which induces produce the positive feedback on the pituitary which induces the LH surge at midcycle. The peak value of estrogen is the LH surge at midcycle. The peak value of estrogen is reached 24-36 hours before ovulation while FSH declines to a reached 24-36 hours before ovulation while FSH declines to a nadir level.nadir level.

LH starts to rise 32-38 hours before ovulation and reaches a LH starts to rise 32-38 hours before ovulation and reaches a peak value 10-12 hours before it. Acting upon its own receptor peak value 10-12 hours before it. Acting upon its own receptor which were induced by the combined effect of FSH and which were induced by the combined effect of FSH and estrogen, LH starts luteinization of the granulosa cells resulting estrogen, LH starts luteinization of the granulosa cells resulting in the production of progesteron within the microenvironment in the production of progesteron within the microenvironment of the preovulatory follicle 24-48 hours before ovulation. of the preovulatory follicle 24-48 hours before ovulation. Gonadotropins released at midcycle are characterized with high Gonadotropins released at midcycle are characterized with high bioactivity and longer half life with increased content of sialic bioactivity and longer half life with increased content of sialic acid.acid.

Progesterone in very small amounts facilitates the positive Progesterone in very small amounts facilitates the positive feedback response of the pituitary to threshold level of feedback response of the pituitary to threshold level of estrogen with enhanced pituitary response to GnRH. In addition estrogen with enhanced pituitary response to GnRH. In addition to this, progesterone is responsible for the FSH surge at to this, progesterone is responsible for the FSH surge at midcycle.midcycle.

FSH has a midcyclic surge as LH but of much lesser FSH has a midcyclic surge as LH but of much lesser amplitude which serve to ensure that a full amplitude which serve to ensure that a full complement of LH receptors is in place in the complement of LH receptors is in place in the granulosa cells.granulosa cells.

Androgens are also produced from the ovary at this Androgens are also produced from the ovary at this stage. The theca component of the other follicles stage. The theca component of the other follicles which fail to achieve full maturity, return to their which fail to achieve full maturity, return to their origin as a component of the ovarian stroma. They origin as a component of the ovarian stroma. They retain their ability to respond to LH stimuli with the retain their ability to respond to LH stimuli with the production of androgen in the ovarian stroma. The production of androgen in the ovarian stroma. The plasma androstenedione rises by 15% and plasma androstenedione rises by 15% and testosterone by 20% at midcycle. This rise in testosterone by 20% at midcycle. This rise in androgens acts locally to assure and complete the androgens acts locally to assure and complete the wave of atresia in the non-dominant follicles and wave of atresia in the non-dominant follicles and may has a systemic effect to increase lipido at may has a systemic effect to increase lipido at midcycle.midcycle.

2.2. Ovulation:Ovulation: Ovulation or follicular rupture is not due to increased Ovulation or follicular rupture is not due to increased

intra-follicular pressure. The escape of the ovum is preceded by intra-follicular pressure. The escape of the ovum is preceded by separation of the oocyte-cumulus cell mass from the rest of the separation of the oocyte-cumulus cell mass from the rest of the follicle to float freely in the antral fluid with massive increase in follicle to float freely in the antral fluid with massive increase in the amount of the fluid. The escape of the ovum is associated the amount of the fluid. The escape of the ovum is associated with degenerative changes of the collagen in the follicular wall with degenerative changes of the collagen in the follicular wall which occurs just prior to ovulation. This is accompanied by which occurs just prior to ovulation. This is accompanied by completion of the oocyte maturation and luteinization. The completion of the oocyte maturation and luteinization. The midcyclic LH surge is the main stimulus to ovulation, but it midcyclic LH surge is the main stimulus to ovulation, but it should be synchronized with oocyte maturation and other should be synchronized with oocyte maturation and other morphological and functional changes within the dominant morphological and functional changes within the dominant follicle. AS the main stimulus for the LH surge is the high follicle. AS the main stimulus for the LH surge is the high estrogen level produced by the dominant follicle, it is the follicle estrogen level produced by the dominant follicle, it is the follicle itself that determines the proper timing of ovulation. In addition itself that determines the proper timing of ovulation. In addition to LH, the FSH surge, estrogen and progesterone all play a role to LH, the FSH surge, estrogen and progesterone all play a role in the process of ovulation through manipulating the activity of in the process of ovulation through manipulating the activity of several non steroid products in the follicle, this may include:several non steroid products in the follicle, this may include:

a)a) LH induced rise in cyclic-AMP overcomes the effect of LH induced rise in cyclic-AMP overcomes the effect of oocyte maturation inhibitor (OMI) and luteinization oocyte maturation inhibitor (OMI) and luteinization inhibitor (LI) which are two non steroid products of the inhibitor (LI) which are two non steroid products of the follicle present in the follicular fluid and serve to inhibit follicle present in the follicular fluid and serve to inhibit premature oocyte maturation and luteinization.premature oocyte maturation and luteinization.

b)b) LH and progesterone stimulate proteolytic enzymes LH and progesterone stimulate proteolytic enzymes (collagenase and plasmin), resulting in the digestion of (collagenase and plasmin), resulting in the digestion of collagen in the follicular wall. This may be mediated via collagen in the follicular wall. This may be mediated via the production of prostaglandins E and F which may act the production of prostaglandins E and F which may act to free lysosomal enzymes.to free lysosomal enzymes.

c)c) Prostaglandins may also stimulate the contraction of Prostaglandins may also stimulate the contraction of smooth muscles which is present in the ovary.smooth muscles which is present in the ovary.

d)d) FSH is a good stimulator for the release of plasminogen FSH is a good stimulator for the release of plasminogen activators which are responsible for the activation of activators which are responsible for the activation of plasminogen to plasmin. FSH stimulates the synthesis of plasminogen to plasmin. FSH stimulates the synthesis of hyaluronic acid whose accumulation is necessary in the hyaluronic acid whose accumulation is necessary in the separation of the oocyte-cumulus cell mass from the rest separation of the oocyte-cumulus cell mass from the rest of the follicle.of the follicle.

The midcyclic increase in LH is short-living The midcyclic increase in LH is short-living and it shortly ends with a decline in the level and it shortly ends with a decline in the level of LH. The exact mechanism is not yet fully of LH. The exact mechanism is not yet fully known, but it may be due to exhaustion of the known, but it may be due to exhaustion of the LH storage in the pituitary, -ve feedback of LH LH storage in the pituitary, -ve feedback of LH itself on the GnRH pulse generator, down itself on the GnRH pulse generator, down regulation of GnRH receptors, or loss of the regulation of GnRH receptors, or loss of the +ve feedback stimulus as estrogen level +ve feedback stimulus as estrogen level plunges as LH reaches its peak with a plunges as LH reaches its peak with a precipitous drop in circulating estrogen level.precipitous drop in circulating estrogen level.

3.3. Luteal phase:Luteal phase: After ovulation and escape of the oocyte with the After ovulation and escape of the oocyte with the

cumulus cell mass to the peritoneal cavity, dramatic cumulus cell mass to the peritoneal cavity, dramatic morphological changes occurs in the remaining part of morphological changes occurs in the remaining part of the follicle within the next 2-3 days converting it to the the follicle within the next 2-3 days converting it to the corpus luteum. The name is derived from deposition of corpus luteum. The name is derived from deposition of lutein, a yellow pigment of fat cells and egg yolk, inside lutein, a yellow pigment of fat cells and egg yolk, inside the granulosa cells which become vacuolated and in the the granulosa cells which become vacuolated and in the theca-lutein cells differentiated from the surrounding theca-lutein cells differentiated from the surrounding theca and stromal cells.theca and stromal cells.

Another very important anatomical change is the Another very important anatomical change is the penetration of the granulosa cells for the first time by penetration of the granulosa cells for the first time by blood capillaries from the underlying theca-lutein layer, blood capillaries from the underlying theca-lutein layer, with filling of the cavity with blood. Vascularization with filling of the cavity with blood. Vascularization reaches its peak 8-9 days after ovulation. This change is reaches its peak 8-9 days after ovulation. This change is very important to deliver LDL to the granulosa cells from very important to deliver LDL to the granulosa cells from which they extract cholesterol needed for which they extract cholesterol needed for steroidogenesis.steroidogenesis.

The cells of the corpus luteum which have been prepared The cells of the corpus luteum which have been prepared during the follicular phase by FSH and estrogen and have a during the follicular phase by FSH and estrogen and have a great number of LH receptors produces great amounts of both great number of LH receptors produces great amounts of both estrogen and progesteron under LH stimulation. Continuos LH estrogen and progesteron under LH stimulation. Continuos LH stimulation at low level is needed to maintain the steroid stimulation at low level is needed to maintain the steroid production by the CL. Progesterone plasma level reaches its production by the CL. Progesterone plasma level reaches its peak level 8 days after the LH surge.peak level 8 days after the LH surge.

Progesterone acts centrally through the hypothalamus Progesterone acts centrally through the hypothalamus to suppress gonadotropin production, and locally it suppress to suppress gonadotropin production, and locally it suppress new follicular growth in the ovary containing the CL. This new follicular growth in the ovary containing the CL. This effect is mediated by depletion of estrogen receptors which is effect is mediated by depletion of estrogen receptors which is needed to support early follicular differentiation. So during the needed to support early follicular differentiation. So during the next cycle, usually the dominant follicle will be present in the next cycle, usually the dominant follicle will be present in the contralateral ovary.contralateral ovary.

The duration of the luteal phase is consistently close to The duration of the luteal phase is consistently close to 14 days from the LH surge to menses. In the absence of 14 days from the LH surge to menses. In the absence of pregnancy, the CL would decline within 9-11 days after pregnancy, the CL would decline within 9-11 days after ovulation with decline in the steroid production. Luteolysis is ovulation with decline in the steroid production. Luteolysis is induced by the high level of estrogen reached in the second induced by the high level of estrogen reached in the second half of the luteal phase. This effect is mediated by estrogen half of the luteal phase. This effect is mediated by estrogen stimulated production of prostaglandins within the ovary stimulated production of prostaglandins within the ovary which uncouple the LH receptor complex from the adenylate which uncouple the LH receptor complex from the adenylate cyclase enzyme across the lipid bilayer of the cell membrane. cyclase enzyme across the lipid bilayer of the cell membrane. IB pregnancy occurs, HCG, produced from the chorion starts IB pregnancy occurs, HCG, produced from the chorion starts to rise 9 days after ovulation to rescue the CL from to rise 9 days after ovulation to rescue the CL from regression.regression.

THE ENDOMETRIUM THE ENDOMETRIUM (UTERINE) CYCLE(UTERINE) CYCLE

The histology of the adult endometrium:The histology of the adult endometrium: The endometrium can be divided into an The endometrium can be divided into an

upper 2/3 functionalis layer and lower 1/3 upper 2/3 functionalis layer and lower 1/3 basalis layer on the basis of morphology and basalis layer on the basis of morphology and function.function.

The purpose of functional layer is to prepare The purpose of functional layer is to prepare for implantation of blastocyst. It is the site for for implantation of blastocyst. It is the site for (1) proliferation, (2) secretion and (3) (1) proliferation, (2) secretion and (3) menstruation.menstruation.

The purpose of basalis layer is to provide the The purpose of basalis layer is to provide the regenerative endometrium following regenerative endometrium following menstrual loss of functionalis.menstrual loss of functionalis.

The histologic changes are based The histologic changes are based on two parts:on two parts:

Endometrial glands.Endometrial glands. Stroma.Stroma.

I.I. Proliferative phase:Proliferative phase: In the proliferative phase, tissue components (glands In the proliferative phase, tissue components (glands

including endothelial cells, stromal cells) demonstrate including endothelial cells, stromal cells) demonstrate proliferation, which peaks on days 8-10 of the cycle, proliferation, which peaks on days 8-10 of the cycle, corresponding to peak estradiol levels in the circulation and corresponding to peak estradiol levels in the circulation and maximal estrogen receptor concentration in the maximal estrogen receptor concentration in the endometrium. This proliferation is marked by increased endometrium. This proliferation is marked by increased mitotic activity and increased nuclear DNA and cytoplasmic mitotic activity and increased nuclear DNA and cytoplasmic RNA synthesis, that is most intense in the functionalis layer RNA synthesis, that is most intense in the functionalis layer in the upper two-thirds of the uterus, the usual site of in the upper two-thirds of the uterus, the usual site of blastocyst implantation.blastocyst implantation.

At the beginning, the endometrium is relatively thin (1-2 At the beginning, the endometrium is relatively thin (1-2 mm). The initially straight narrow and short endometrial mm). The initially straight narrow and short endometrial glands changes to longer tortuous structure. The glands changes to longer tortuous structure. The organization changes: low columnar pattern early organization changes: low columnar pattern early proliferative (5th day of the cycle) to a pseudo-stratified proliferative (5th day of the cycle) to a pseudo-stratified before ovulation (12th day of the cycle); the stroma is a before ovulation (12th day of the cycle); the stroma is a dense compact layer throughout this time. Vascular dense compact layer throughout this time. Vascular structure is infrequently seen.structure is infrequently seen.

II.II. Secretory phase:Secretory phase: The corpus luteum produces large quantities of progesterone The corpus luteum produces large quantities of progesterone

which induces secretory changes in the glands and swelling of which induces secretory changes in the glands and swelling of stromal cells. There is a rich blood supply and the capillaries stromal cells. There is a rich blood supply and the capillaries become sinusoidal with little intervening stroma. become sinusoidal with little intervening stroma.

The first histologic sign that ovulation has occurred is the The first histologic sign that ovulation has occurred is the appearance of subnuclear intracytoplasmic glycogen vacuoles in appearance of subnuclear intracytoplasmic glycogen vacuoles in the glandular epithelium on cycle days 17-18. Giant the glandular epithelium on cycle days 17-18. Giant mitochondria and the "nucleolar channel system" appear in the mitochondria and the "nucleolar channel system" appear in the gland cells. Individual components of the tissue continue to gland cells. Individual components of the tissue continue to display growth, but confinement in a fixed structure leads to display growth, but confinement in a fixed structure leads to progressive tortuosity of glands and intensified coiling of the progressive tortuosity of glands and intensified coiling of the spiral vessels. These structural alterations are soon followed by spiral vessels. These structural alterations are soon followed by active secretion of glycoproteins and peptides into the active secretion of glycoproteins and peptides into the endometrial cavity. Transudation of plasma also contributes to endometrial cavity. Transudation of plasma also contributes to the endometrial secretions. The peak secretory level is reached 7 the endometrial secretions. The peak secretory level is reached 7 days after the midcycle gonadotropin surge, coinciding with the days after the midcycle gonadotropin surge, coinciding with the time of blastocyst implantation. time of blastocyst implantation.

Of note the endometrial height is fixed at roughly Of note the endometrial height is fixed at roughly its preovulatory extent (5-6 mm) despite continued its preovulatory extent (5-6 mm) despite continued availability of estrogen. Epithelial proliferation availability of estrogen. Epithelial proliferation ceases 3 days after ovulation. This restraint or ceases 3 days after ovulation. This restraint or inhibition is believed to be induced by inhibition is believed to be induced by progesterone.progesterone.

Implantation phase (Late Secretory); ie 7th - 13th Implantation phase (Late Secretory); ie 7th - 13th post ovulation (21th - 27th of cycle) whereby the post ovulation (21th - 27th of cycle) whereby the distended tortuous secretory glands have been distended tortuous secretory glands have been most prominent with little intervening stoma. The most prominent with little intervening stoma. The time of implantation is in days 21-22 of the cycle. time of implantation is in days 21-22 of the cycle. The predominant morphologic feature is edema of The predominant morphologic feature is edema of endometrial stroma secondary to the estrogen- and endometrial stroma secondary to the estrogen- and progester one-mediated increase in prostaglandin progester one-mediated increase in prostaglandin production. By day 13-14, post-ovulatory: the production. By day 13-14, post-ovulatory: the endometrium is divided into 3 distinct zones: 1/4 endometrium is divided into 3 distinct zones: 1/4 unchanged basalis, 1/2 stratum spongiosum, 1/4 unchanged basalis, 1/2 stratum spongiosum, 1/4 stratum compactum superficial layer. stratum compactum superficial layer.

III.III. Menstrual phase:Menstrual phase: The menstrual endometrium is a relatively thin but dense The menstrual endometrium is a relatively thin but dense

tissue. It is composed of the stable, nonfunctioning basalis tissue. It is composed of the stable, nonfunctioning basalis component and a variable, but small, amount of residual component and a variable, but small, amount of residual stratum spongiosum.The menstrual endometrium is a stratum spongiosum.The menstrual endometrium is a transitional state bridging the more dramatic proliferative transitional state bridging the more dramatic proliferative and exfoliative phases of the cycle. Its density implies that and exfoliative phases of the cycle. Its density implies that the shortness of height is not entirely due to the shortness of height is not entirely due to desquamation. Collapse of the supporting matrix also desquamation. Collapse of the supporting matrix also contributes significantly to the shallowness. Nevertheless, contributes significantly to the shallowness. Nevertheless, as much as two-thirds of the functioning endometrium is as much as two-thirds of the functioning endometrium is lost during menstruation. The more rapid the tissue loss, lost during menstruation. The more rapid the tissue loss, the shorter the duration of flow. Delayed or incomplete the shorter the duration of flow. Delayed or incomplete shedding is in association with heavier flow and greater shedding is in association with heavier flow and greater blood lossblood loss

Menstruation (Bleeding) mechanism:Menstruation (Bleeding) mechanism: The unique features of primate females who menstruate is the The unique features of primate females who menstruate is the

existence of spiral arteries (end arteries,with no anastomosis) existence of spiral arteries (end arteries,with no anastomosis) supplying the superficial layer of the endometrium (funtionalis supplying the superficial layer of the endometrium (funtionalis layer), thus making the superficial layer of the endometrium layer), thus making the superficial layer of the endometrium vulnerable to ischaemia, but also facilitating hemostasis. vulnerable to ischaemia, but also facilitating hemostasis.

In the proliferative phase, the spiral arterioles grow upwards from In the proliferative phase, the spiral arterioles grow upwards from the basal to more superficial layers of the endometrium, where a the basal to more superficial layers of the endometrium, where a capillary network develops.capillary network develops.

In the luteal phase, there is a marked increase in length and In the luteal phase, there is a marked increase in length and coiling of the spiral arterioles which will become more dilated.coiling of the spiral arterioles which will become more dilated.

Premenstrually, the endometrial glands empty secretions, the fluid Premenstrually, the endometrial glands empty secretions, the fluid from the stroma is resorbed, the endometrium shrinks (deflated), from the stroma is resorbed, the endometrium shrinks (deflated), and the spiral arterioles become even more coiled up to 8 loops. and the spiral arterioles become even more coiled up to 8 loops. At the same time, gaps appear between the endothelial cell of the At the same time, gaps appear between the endothelial cell of the spiral arterioles and the associated thin walled veins and spiral arterioles and the associated thin walled veins and leucocytes migrate through the gaps into the stroma which leucocytes migrate through the gaps into the stroma which appears to be undergo disintegration.appears to be undergo disintegration.

Progesterone has a stabilizing effect and estrogen labilizing effect Progesterone has a stabilizing effect and estrogen labilizing effect on lysosomes in the endometrium. The withdrawal of progesterone on lysosomes in the endometrium. The withdrawal of progesterone preceding menstruation probably causes breakdown of lysosomes preceding menstruation probably causes breakdown of lysosomes and release of phsopholipase A2. This in turn causes the formation and release of phsopholipase A2. This in turn causes the formation of large amounts of arachidonic acid from phospholipids in the cell of large amounts of arachidonic acid from phospholipids in the cell wall and initiates the prostaneid cascade and the synthesis of wall and initiates the prostaneid cascade and the synthesis of PGF2PGF2 and PGE2 and PGI2. The sudden increase of prostaglandins, and PGE2 and PGI2. The sudden increase of prostaglandins, particularly PGF2particularly PGF2 is probably responsible for the spasmodic is probably responsible for the spasmodic contraction of the spiral arterioles and for menstruation.contraction of the spiral arterioles and for menstruation.

Immediately before menstruation, the spiral arteries constrict Immediately before menstruation, the spiral arteries constrict intensely for a period of 4-24 hours and then dilate with a massive intensely for a period of 4-24 hours and then dilate with a massive extravasation of erythrocytes into the stroma of endometrium. extravasation of erythrocytes into the stroma of endometrium.

Blood initially spurts from the open end of spiral arterioles but Blood initially spurts from the open end of spiral arterioles but normally stops rapidly. Bleeding occurs from the coalesced blood normally stops rapidly. Bleeding occurs from the coalesced blood lakes and from the torn ends of capillaries and veins, bleeding from lakes and from the torn ends of capillaries and veins, bleeding from the latter being slower and continuing longer. Approximately 75% of the latter being slower and continuing longer. Approximately 75% of menstrual blood is arterial and 25% is venous. Though the menstrual blood is arterial and 25% is venous. Though the proportion may change in women with menorrhagia, only about proportion may change in women with menorrhagia, only about one-quarter of the total endometrium is shed; the majority involutes one-quarter of the total endometrium is shed; the majority involutes and is reabsorbed, as in animal species which do not menstruate.and is reabsorbed, as in animal species which do not menstruate.

Menstrual blood contains aggregations of erythrocytes, degraded Menstrual blood contains aggregations of erythrocytes, degraded and exhausted platelets, small amounts of fibrin and large amounts and exhausted platelets, small amounts of fibrin and large amounts of fibrin degradation products, suggesting that the haemostatic of fibrin degradation products, suggesting that the haemostatic plugs and any blood clots that may form undergo fibrinolysis and plugs and any blood clots that may form undergo fibrinolysis and rapidly disintegrate. An excess of fibrinolytic activity in the rapidly disintegrate. An excess of fibrinolytic activity in the endometrium might well impair haemostatic plug formation in the endometrium might well impair haemostatic plug formation in the spiral arterioles and would provide a ready explanation for spiral arterioles and would provide a ready explanation for excessive menstrual blood loss.excessive menstrual blood loss.

Menstrual blood stoppage mechanism (Haemostasis):Menstrual blood stoppage mechanism (Haemostasis): Hemostatic plug function of aggregated platelets and fibrin Hemostatic plug function of aggregated platelets and fibrin

in the spiral arterioles, which is small and incomplete in the spiral arterioles, which is small and incomplete compared with those in skin wounds with onion skin like compared with those in skin wounds with onion skin like allowing intermittent blood flow before complete occlusion.allowing intermittent blood flow before complete occlusion.

Vasoconstriction of spiral arteries together with swelling of Vasoconstriction of spiral arteries together with swelling of endothelial cells which completely occlude the arterioles endothelial cells which completely occlude the arterioles occurs in the 2nd day of menstruation and is considered the occurs in the 2nd day of menstruation and is considered the most important mechanism controlling menstrual blood. most important mechanism controlling menstrual blood. Prostaglandins play vital part.Prostaglandins play vital part.

Re-epithelization commences from the basal glands, Re-epithelization commences from the basal glands, proceeds rapidly, and is usually completed by third or proceeds rapidly, and is usually completed by third or fourth day, which depends on the rate of estrogen fourth day, which depends on the rate of estrogen stimulation, which in turn, depends on the rate of growth of stimulation, which in turn, depends on the rate of growth of the follicles developing in the ovaries. It starts from the the follicles developing in the ovaries. It starts from the region of the isthmus and cornual recesses of the ostea of region of the isthmus and cornual recesses of the ostea of the fallopian tube. Furthermore, the stromal layer the fallopian tube. Furthermore, the stromal layer contributes important autocrine and paracrine factors for contributes important autocrine and paracrine factors for growth and migration, mainly in response to injury rather growth and migration, mainly in response to injury rather than hormonal effect as hormone levels are at their nadir.than hormonal effect as hormone levels are at their nadir.

The uterus as an endocrinal organ:The uterus as an endocrinal organ: The uterus is a dynamic as many endometrial products had The uterus is a dynamic as many endometrial products had

been verified. Lipids as Prostaglandins, Thromboxanes, been verified. Lipids as Prostaglandins, Thromboxanes, Leukotrienes has been identified to be secreted from Leukotrienes has been identified to be secreted from stromal & endometrial cell with various functions (see stromal & endometrial cell with various functions (see below). Cytokines as Interleukin-la, lnterleukin-1B, below). Cytokines as Interleukin-la, lnterleukin-1B, lnterleukin-6, Interferon-g, Colony-stimulating factor-1, lnterleukin-6, Interferon-g, Colony-stimulating factor-1, Tumor necrosis factor-a Leukemia,-inhibiting factor were Tumor necrosis factor-a Leukemia,-inhibiting factor were also identified. List of other peptides secreted from also identified. List of other peptides secreted from endometrial cell with various functions as enzymes & endometrial cell with various functions as enzymes & enzymes inhibitors, angiogenic, vasoactive , hemostatic & enzymes inhibitors, angiogenic, vasoactive , hemostatic & growth factors includes : [ Prolactin, Relaxin, Prorenin and growth factors includes : [ Prolactin, Relaxin, Prorenin and rennin, Endorphin, Endothelin-1,Corticotropin-releasing rennin, Endorphin, Endothelin-1,Corticotropin-releasing hormone, Fibronectin, Uteroglobin, Lipocortin-1, Parathyroid hormone, Fibronectin, Uteroglobin, Lipocortin-1, Parathyroid hormone-like protein, Integrins, Epidermal growth factor hormone-like protein, Integrins, Epidermal growth factor family [EGF / Heparin-binding EGF / TGF-a ], Insulin-like family [EGF / Heparin-binding EGF / TGF-a ], Insulin-like growth factor family [IGF-l / IGF-ll / IGFBPs1-6 ] , Platelet-growth factor family [IGF-l / IGF-ll / IGFBPs1-6 ] , Platelet-derived growth factor, Transforming growth factor-B, derived growth factor, Transforming growth factor-B, Fibroblast growth factor, Vascular endothelial growth Fibroblast growth factor, Vascular endothelial growth factor ].factor ].

Role of Prostaglandins:Role of Prostaglandins: In the proliferative phase the endometrium synthesizes In the proliferative phase the endometrium synthesizes

equal amounts of PGF2equal amounts of PGF2 and PGE2 1:1, but in the luteal and PGE2 1:1, but in the luteal phase the level of PGF2phase the level of PGF2 progressively increases under the progressively increases under the influence of estradiol and progesterone 2:1 in menstrual influence of estradiol and progesterone 2:1 in menstrual fluid, so that vasoconstriction and platelet - aggregatory fluid, so that vasoconstriction and platelet - aggregatory action predominates. The myometrium produces action predominates. The myometrium produces considerable amounts of PGI2 synthesized from considerable amounts of PGI2 synthesized from endoperoxides produced in the endometrium which diffuse endoperoxides produced in the endometrium which diffuse to myometrium, producing vasodilation and inhibiting to myometrium, producing vasodilation and inhibiting platelet aggregation.platelet aggregation.

In normal menstruation, it is postulated that the PGF2In normal menstruation, it is postulated that the PGF2 synthesized in the endometrium first produces synthesized in the endometrium first produces vasoconstriction of spiral arterioles, and as a result, an vasoconstriction of spiral arterioles, and as a result, an increased proportion of the endoperoxides is produced from increased proportion of the endoperoxides is produced from arachidonic acid by prostaglandin synthetase deviated into arachidonic acid by prostaglandin synthetase deviated into the myometrium, which, then produces a surge of PGI2. the myometrium, which, then produces a surge of PGI2. This surge may then diffuse back into the endometrium, This surge may then diffuse back into the endometrium, producing the dilatation which follows the vasoconstriction producing the dilatation which follows the vasoconstriction of spiral arterioles immediately preceding the onset of of spiral arterioles immediately preceding the onset of menstruation.menstruation.

At the end of the non-fertile cycle, At the end of the non-fertile cycle, endoperoxides generated from free endoperoxides generated from free arachidonic acid, released from membrane arachidonic acid, released from membrane phospholipid stores by the action of phospholipid stores by the action of phospholipase A2, are converted phospholipase A2, are converted predominatly to prostaglandin F2-predominatly to prostaglandin F2-Endoperoxides may also be transported to Endoperoxides may also be transported to the myometrium, where they are converted the myometrium, where they are converted to prostacyclin. Prostacyclin of myometrial to prostacyclin. Prostacyclin of myometrial origin may act to prevent platelet origin may act to prevent platelet aggregation and stimulate vasodilation aggregation and stimulate vasodilation within the endometrium at menstruation.within the endometrium at menstruation.

Role of Leukotrines:Role of Leukotrines: They are produced predominantly by They are produced predominantly by

leucocytes. Excessive infiltration of the leucocytes. Excessive infiltration of the endometrium with leucocytes is seen in endometrium with leucocytes is seen in menorrhagia with IUDs, and the degree of menorrhagia with IUDs, and the degree of menstrual blood loss is roughly proportional to menstrual blood loss is roughly proportional to the degree of infiltration. Excessive production the degree of infiltration. Excessive production of leukotrines is responsible for IUCD of leukotrines is responsible for IUCD menorrhagia, if the arachidonic acid is menorrhagia, if the arachidonic acid is deviated from the cyclo-oxygenase to the deviated from the cyclo-oxygenase to the lipoxygenase pathway.lipoxygenase pathway.

Enzymes & uterus:Enzymes & uterus: The endometrium and cervix are sites of marked The endometrium and cervix are sites of marked

fibrinolytic activity and plasminogen activators fibrinolytic activity and plasminogen activators have been demonstrated in the myometrium, have been demonstrated in the myometrium, endometrium and menstrual blood. The endometrium and menstrual blood. The concentration of plasminogen activators in concentration of plasminogen activators in menstrual blood is maximal on the first day of menstrual blood is maximal on the first day of bleeding and is higher in women with excess bleeding and is higher in women with excess menstrual blood loss. It is also much higher in menstrual blood loss. It is also much higher in samples collected from the uterus than from the samples collected from the uterus than from the vagina, suggesting that the activators are rapidly vagina, suggesting that the activators are rapidly consumed and explaining why clots may form in consumed and explaining why clots may form in the vagina but rarely do so in the uterus.the vagina but rarely do so in the uterus.

Endometrial Cycle: Clinical prospective:Endometrial Cycle: Clinical prospective: A normal menstrual cycle last from 21 to 35 days with 2 to 6 A normal menstrual cycle last from 21 to 35 days with 2 to 6

days of flow & an average blood loss of 20-60ml. In the days of flow & an average blood loss of 20-60ml. In the extremes of reproductive age, menstrual cycles are extremes of reproductive age, menstrual cycles are characterized by a higher percentage of anovulatory or characterized by a higher percentage of anovulatory or irregularly timed cycles. The diagnosis and management of irregularly timed cycles. The diagnosis and management of abnormal menstrual function must be based on an abnormal menstrual function must be based on an understanding of the physiologic mechanisms involved in the understanding of the physiologic mechanisms involved in the regulation of the normal cycle.regulation of the normal cycle.

Primary dysfunctional bleeding (PDB), including essential Primary dysfunctional bleeding (PDB), including essential menorrhagia, probably results from a number of different menorrhagia, probably results from a number of different factors, including disturbances in eicosanoid metabolism and factors, including disturbances in eicosanoid metabolism and in fibrinolytic and lysosomal enzyme systems of the in fibrinolytic and lysosomal enzyme systems of the endometrium. This disturbance may be primarily in the endometrium. This disturbance may be primarily in the endometrium or secondary to endocrine changes originating endometrium or secondary to endocrine changes originating in the ovary, pituitary and hypothalamus.in the ovary, pituitary and hypothalamus.

Excessive menstrual blood loss (MBL) could be due to the Excessive menstrual blood loss (MBL) could be due to the increased formation of lysosomes with an increased increased formation of lysosomes with an increased synthesis of phospholipase A2, arachidonic acid and synthesis of phospholipase A2, arachidonic acid and prostaglandin at menstruation as is believed to occur in prostaglandin at menstruation as is believed to occur in ovulatoryDUB. Marked increase in both plasminogen ovulatoryDUB. Marked increase in both plasminogen activators and in fibrinolytic activity plasmin in menstrual activators and in fibrinolytic activity plasmin in menstrual blood in case of DUB particularly with IUDs. This is reversed blood in case of DUB particularly with IUDs. This is reversed by anti-fibrinolytic drugs Tranexamic acid.by anti-fibrinolytic drugs Tranexamic acid.

Interaction between thrombin formation and fibrinolysis of Interaction between thrombin formation and fibrinolysis of hemostatic plugs and the action of prostanoids including hemostatic plugs and the action of prostanoids including PGI2 and TXA2 and that the blood clotting fibrinolytic and PGI2 and TXA2 and that the blood clotting fibrinolytic and prostanoid systems are closely linked.prostanoid systems are closely linked.

Clinical implication of Endometrial dating: The precise Clinical implication of Endometrial dating: The precise nature of the histologic changes that occur in secretory nature of the histologic changes that occur in secretory endometrium relative to LH surge allows the assessment of endometrium relative to LH surge allows the assessment of the “normalcy” of endometrial development. Any large the “normalcy” of endometrial development. Any large discrepancy (more than 2-day lag time) is termed a Luteal discrepancy (more than 2-day lag time) is termed a Luteal phase defect & has been linked to both failure of phase defect & has been linked to both failure of implantation & early pregnancy loss. To perform such implantation & early pregnancy loss. To perform such diagnostic test, determine ovulation timing then take an diagnostic test, determine ovulation timing then take an endometrial biopsy 10-12 days postovulation.endometrial biopsy 10-12 days postovulation.

Also note the clinical implication of endometrial thickness Also note the clinical implication of endometrial thickness (height) by vaginal US.(height) by vaginal US.

The cervical cycle:The cervical cycle: Progesterone raises the tone of the muscles of Progesterone raises the tone of the muscles of

the isthmus and internal os so the cervical the isthmus and internal os so the cervical 'sphincter' is tighter and more competent during 'sphincter' is tighter and more competent during the luteal than during the follicular phase.the luteal than during the follicular phase.

The glandular elements proliferate during the The glandular elements proliferate during the follicular phase and the epithelial cells become follicular phase and the epithelial cells become taller. Under the influence of oestrogens the taller. Under the influence of oestrogens the glands actively secrete a mucus which will stretch glands actively secrete a mucus which will stretch into threads measuring more than 6.5 cm, and into threads measuring more than 6.5 cm, and even 10-15 cm, at the time of ovulation. even 10-15 cm, at the time of ovulation. Spinnbarkeit is the basis of the thread test for Spinnbarkeit is the basis of the thread test for estrogen in circulation. During the follicular phase estrogen in circulation. During the follicular phase the cervical mucus absorbs water and salts and, the cervical mucus absorbs water and salts and, when allowed to dry, deposits crystals of sodium when allowed to dry, deposits crystals of sodium chloride and potassium chloride in a chloride and potassium chloride in a characteristic pattern which suggests the fronds characteristic pattern which suggests the fronds of a fern (see diagnostic procedures).of a fern (see diagnostic procedures).

At the time of ovulation, the secretion is so profuse At the time of ovulation, the secretion is so profuse that it may be noticeable as a vaginal discharge – that it may be noticeable as a vaginal discharge – the “ovulation cascade”. Its special character at the “ovulation cascade”. Its special character at this time makes for its easy penetration by this time makes for its easy penetration by spermatozoa. This property is related to its low spermatozoa. This property is related to its low content of protein.content of protein.

During the luteal phase, the cervical glands become During the luteal phase, the cervical glands become more branched and their secretion changes its more branched and their secretion changes its physical and chemical properties. The mucus physical and chemical properties. The mucus becomes more viscous and forms a more secure becomes more viscous and forms a more secure cervical plug. It loses, its ability to stretch without cervical plug. It loses, its ability to stretch without breaking and resists penetration by spermatozoa. breaking and resists penetration by spermatozoa. These changes are brought about by progesterone These changes are brought about by progesterone and are related to an increase in the amount of and are related to an increase in the amount of protein in the mucus and to the presence of protein in the mucus and to the presence of phospholipids.phospholipids.

The vaginal cycle:The vaginal cycle: The cyclical changes occur in the vaginal The cyclical changes occur in the vaginal

epithelium are better seen in smears of epithelium are better seen in smears of desquamated cells. The unstimulated vagina desquamated cells. The unstimulated vagina shows relatively small basal type cells with shows relatively small basal type cells with healthy nuclei. These and intermediate basophil healthy nuclei. These and intermediate basophil forms are also seen in vaginal smears taken in the forms are also seen in vaginal smears taken in the early follicular phase. The fully oestrogemc smear, early follicular phase. The fully oestrogemc smear, evident during the late follicular phase, contains a evident during the late follicular phase, contains a preponderance of large cornified epithelial cells preponderance of large cornified epithelial cells with pyknotic nuclei. These stain pink with eosin. with pyknotic nuclei. These stain pink with eosin. During the luteal phase the smear shows evidence During the luteal phase the smear shows evidence of increased desquamation, many of the cells of increased desquamation, many of the cells having rolled edges, and is characterized by the having rolled edges, and is characterized by the reappearance of clumps of intermediate cells and reappearance of clumps of intermediate cells and the presence of leucocytes. The maturation index, the presence of leucocytes. The maturation index, which is the percentage of superficial, which is the percentage of superficial, intermediate and parabasal cells in a vaginal intermediate and parabasal cells in a vaginal smear is used as a measure of the levels of smear is used as a measure of the levels of hormones in circulation. It is a useful guide but is hormones in circulation. It is a useful guide but is not so precise as assaying the hormones in blood.not so precise as assaying the hormones in blood.

Cyclical changes in the tube:Cyclical changes in the tube: The muscle of the fallopian tube behaves like the The muscle of the fallopian tube behaves like the

myometrium in that it shows increased movement myometrium in that it shows increased movement about the time of ovulation. This is an estrogen about the time of ovulation. This is an estrogen effect. The increased cilial activity at that time. effect. The increased cilial activity at that time. These changes are timed to propel the ovum These changes are timed to propel the ovum towards the uterus.towards the uterus.

The follicular phase is marked by slight The follicular phase is marked by slight proliferation, and this continues up to the proliferation, and this continues up to the premenstrual phase when it regresses. During premenstrual phase when it regresses. During menstruation there is further shrinkage and slight menstruation there is further shrinkage and slight shedding of the surface epithelium.shedding of the surface epithelium.

The secretory activity of the tubes is also cyclical, The secretory activity of the tubes is also cyclical, being highest just before ovulation and in response being highest just before ovulation and in response to oestrogen. Progesterone may also play a part in to oestrogen. Progesterone may also play a part in this but the consensus of opinion is that hormone this but the consensus of opinion is that hormone reduces the amount of the secretion.reduces the amount of the secretion.