The menstrual cycle

 1st day of vaginal bleeding is considered Day 1 of the menstrual cycle.

 It generally lasts 28 days.
 It can be divided in:
o Preovulatory phases (Follicular and Proliferative)
o Ovulation
o Postovulatory phases (Luteal and Secretory)
 For most women, the postovulatory phase is stable lasting 13-14 days. Variations in normal cycle
length generally results from a variable duration of the preovulatory phase.
o In study involving >2,700 women found that the menstrual cycle is most variable during
the first 2 years following menarche and 3 years preceding menopause, and is least
variable between 20-40 years of age.

Embriology of the ovary

 3rd week gestation: primordial germ cells can be seen in the yolk sac
 6th week gestation: these cells begin their migration into the gonadal ridge to generate the
primary sex cords
 The ovaries and testes are indistinguishable by histologic criterial until weeks 10-11 of fetal life.
 12th week gestation: subset of oogonia will enter meiosis to become primary oocytes. These are
surrounded by a single layer of flattened granulosa cells, creating the primordial follicle. All
oogonia will develop into primary oocytes or become atretic. Oocytes cannot be g generated
postnatally.
 20th week of gestation: 6-7 million oogonia are present in the ovary
 Birth: 1-2 million of oogonia are present in the ovary
 Start of puberty: <400,000 are present I the ovary

Oocyte maturation. Buscar meiosis I y II en oocytes

 The primary oocytes are arrested in development at prophase I.

 Meiotic progression resumes each month in a cohort of follicles
 Meisosi I is then completed in the oocyte destined for ovulation in response to the LH surge.
 Meiosis II begins and the process is arrested in metaphase II and is only completed if the ovum is
fertilized.

Stromal cells

Ovarian stroma contains interstitial cells, contractile cells and connective tissue cells.

 Connective tissue cells: provide structural support to the ovary

 Interstitial cells: surround a developing follicle and differentiate into theca cells. Under
gonadotropin stimulation, these cells increase in size and develop lipid stores, characteristic of
steroid-producing cells
  Hilum cells: another group of the interstitial cells. These resemble testicular Leyding cells. Their
hyperplasia or neoplasic changes may result in excess testosterone secretion and virilization.
Their normal role is unknown.

Ovarian hormone production

 The normal ovary synthesizes and secretes Estrogens, Androgens and Progesterone, stimulated
by pituitary gonadotropins FSH and LH.
 The most important products of the ovary are the Progesterone and Estradiol.
 The ovary also secretes Estrone, androstenedione, testosterone, 17α-hydroxyprogesterone.
 Sex steroid hormones prepare the uterus for implantation of a fertilized ovum. If this does not
occur, ovarian steroidogenesis declines, the endometrium degenerates and menstruation
ensues.

Two-cell theory of ovarian Steroidogenesis.

 Ovarian Estrogen synthesis requires the combined action of LH and FSH on two cell types (Theca
and Granulosa cells).
o LH-receptor expression is limited to thecal cells
o FSH-receptor expression is limited to the granulosa cells
o Until the late antral stage of follicular development.
 Theca cells…
o Express all of the enzymes needed to synthesize Androstenedione
o This includes high levels of CYP 17 gene expression, whose enzyme product catalyzes 17-
hydroxilation, the rate limiting step in the onversion of Progesterone → Androgens.
 Granulosa cells…
o Lack the enzyme that catalyzes the 17-hydroxilation, so they are incapable of producing
the androgenic precursor needed to produce estrogens. Therefore they rely on the
theca cells.
o Have high levels of aromatase activity in response to FSH stimulation, in contrast to
theca cells.
 In response to LH stimulation, theca cells synthesize the androgens androstenedione and
testosterone. These androgens are secreted into the extracellular fluid and difuse across the
basement membrane to the granulosa cells to provide precursor for estrogen production.
 These cells efficiently convert androgens to estrogens, primarily the potent estrogen Estradiol.

Steroidogenesis across lifespan

In utero

 8 weeks of gestation: the fetal human ovary has the capacity to produce small amounts of
estrogens
 During the 2nd trimester: the plasma levels of gonadotropins rise to levels similar to those
observed in menopause
 Fetal hypothalamic-pituitary axis continues to mature during this time, becoming more sensitive
to the high circulating levels of estrogen and progesterone secreted by the placenta.
 Prior to birth and in response to these high steroid levels, fetal gonadotropins fall to low levels
After delivery

 Gonadotropin levels in the neonate rise abruptly due to separation from the placenta and
subsequent freedom from the placental steroid inhibition
 The elevated gonadotropin levels persist for the first few months of life and then decline to low
levels in early childhood

Puberty

 An early sign of puberty is sleep-associated increase in LH secretion

 Over time, increased gonadotropin secretion is noted throughout the day.
 An increased FSH to LH ratio is typical in the menarchal girl and postmenopausal woman
 Increased gonadotropin levels stimulate ovarian estradiol production.
 The rise in estrogen levels prompts the growth spurt, maturation of the female internal and
external genitalia and development of a female habitus including pubertal breast enlargement
(thelarche)
 The activation of the pituitry-adrenal axis results in an increase in adrenal androgen production
and the associated pubertal development of axillary and pubic hair (adrenarche or pubarche)
 Increased gonadotropin levels ultimately lead to ovulation and subsequent menses.

During the reproductive years

 LH exceeds FSH levels, inverting this FSH to LH ratio seen in puberty.

Following menopause

 The postmenopausal ovary contains only few follicles resulting in a plasma estrogen and inhibin
levels decrease markedly after cessation of ovulatory cycles.
 Though loss of this negative feedback, LH and FSH levels are strikingly elevated.
o Elevated LH levels can stimulate production of C-19 steroids (mainly androstenedione)
in ovarian stromal cells
o This ovarian-derived androstenedione and adrenal androgens can be converted to
Estrone by peripheral tissues. Estrone is the principal estrogen in the postmenopausal
women
o The major site for the conversion of androstenedione to estrone is adipose tissue.
Peripheral conversion of circulating androstenedione to estrone is directly correlated to
body weight.
o These low circulating estrogen levels are usually not adequate to protect against bone
loss

Gonadal peptides

 3 gonadal peptides modulate gonadotrope activity in addition to effects within the ovary
o Inhibin: decreases gonadotrope function
o Activin: stimulates gonadotrope function
o Follistatin: suppresses FSH-ß gene expression, most likely by binding to and thereby
preventing the of activing with its receptor
  These gonadal peptides are expressed in the pituitary, ovary, testes, placenta, brain, adrenal
gland, liver, kidney and bone marrow to provide diverse tissue-specific functions.
 Activin and Follistatin most likely act as autocrine/paracrine actors in the tissues in which they
are expressed.
 Ovarian-derived Inhibins circulate in significant concentrations and are believed to be critical for
negative feedback to gonadotropin gene expression
o During the early follicular phase, FSH stimulates the secretion of Inhibin B by the
granulosa cells
o Increasing levels of circulating Inhibin B blunt later FSH secretion in the follicular phase
o During the Luteal phase, regulation of Inhibin production comes under the control of LH
and switches from Inhibin B to Inhibin A
o Inhibin B levels peak with the LH surge, whereas Inhibin A levels peak a few days later, in
the midluteal phase
o All Inhibin levels decline with the loss of luteal function and remain low during the
luteal-follicular transition and early follicular phase
o The inverse relationship between circulating Inhibin and FSH secretion is consistent with
a negative feedback role (Inhibin regulating FSH secretion)
 Insulin-like growth factors also mediate ovarian function
o Only IGF-II is involved in primordial follicle development, but both IGF-I and II stimulate
growth of secondary follicles
o Gonadotropins stimulate IGF-II production in theca cells, granulosa cells and luteinized
granulosa cells
o Receptors for IGF are expressed on the theca and granulosa cells, supporting an
autocrine/paracrine action in the follicle
o FSH also mediates expression of IGF-binding proteins, allowing an additional fine-
turning of Intrafollicular activity

Follicular development

Follicle stages

 Development begins with primordial follicles that were generated during fetal life.
o These follicles consist of an oocyte arrested in Prophase I surrounded by a single layer of
flattened granulosa cells.
o These follicles are separated from the stroma by a thin basement membrane
o Preovulatory follicles are avascular. As such, they are critically dependent on diffusion
and on the later development of gap junctions for obtaining nutrients and clearing
metabolic waste. Diffusion also allows passage of steroid precursor from the theca to
the granulosa layer
 Primary follicle stage:
o Granulosa cells of developing follicles become cuboidal and increase in number to form
a pseudostratified layer.
o Intercellular gap junctions develop between adjacent granulosa cells and between
granulosa cells and the developing oocyte. These connections allow the passage of
nutrients, ions and regulatory factors between cells. Gap junctions also allow cells
 without gonadotropin receptors to receive signals from cells with receptor expression
(the hormone-mediated effect can be transmitted throughout the follicle)
o The oocyte begins to secrete products to form an acellular coat known as the zona
pellucida. The human version contains at least 3 proteins (ZP1, ZP2, ZP3).
 On the acrosome head of the sperm, there is a receptor that recognizes ZP3.
This interaction releases acrosomal contents that permit penetration of the
zona pellucida and ovum fertilization.
 Enzymes released from the acrosome induce alterations in ZP2 that result in the
hardening of the coat, that prevents fertilization of the oocyte by more than one
sperm
 Secondary follicle (Preantral):
o Includes the final growth of the oocyte and further increase in granulosa cell number
o The stroma around the granulosa cell layer differentiates into the theca interna and
theca externa
 Tertiary follicle (Antral follicles)
o Form from ongoing development in selected oocytes.
o Follicular fluid collets between the granulosa ells, ultimately producing a fluid-filled
space known as the Antrum.
o Granulosa cells in the antral follicle are histologically and functionally divided into 2
groups.
 Granulosa cells surrounding the oocyte form the cumulus oophorus
 Granulosa cells surrounding the antrum are the mural granulosa cells
o Antrum fluid consists of a plasma infiltrate and factors secreted by the granulosa cells.
 This locally produced factors (estrogen, growth factors) are present in
substantially higher concentrations in follicular fluid than in the circulation and
are likely critical for successful follicular maturation
o Further accumulation of antral fluid results in a rapid increase in follicular size and
development to a preovulatory or Graaf follicle.
 Early stages of development (Up to secondary follicle) do NOT require gonadotropin stimulation
and thus are “Gonadotropin-independent)
 Final follicular maturation requires adequate amounts of circulating LH and FSH and thus are
“Gonadotropin-dependent”

Concept of a selection window

 The ovulatory follicle is recruited from a cohort that began development 2-3 cycles prior to the
ovulatory cycle.
 Each month a cohort of follicles begins a phase of semisynchronous growth. The sizes of this
cohort appears to be proportional to the number of inactive primordial follicles within the
ovaries (3-11 follicles per ovary in young woman)
 Most follicles will die as they will not be at an appropriate stage of development during the
selection window
 During the luteal-follicular transition, a small increase in FSH levels is responsible for selection of
the single dominant follicle that will ultimately ovulate
  Estrogen levels increase with increased follicular size, enhance the effect on FSH on granulosa
cells, and create a feed-forward action on follicles that produce estrogens.
 Intrafollicular levels of the IGF are believed to be synergize with FSH to help select the dominant
follicle. Elevated levels of vascular endothelial growth factor (VEGF) have been observed around
the follicle that will be selected.
 Granulosa cells also produce Inhibin B, which passes from the follicle into the plasma and
specifically inhibits the release of FSH, but not of LH by the anterior pituitary.
 The combined production of estradiol and Inhibin B by the dominant follicle results in the
decline of follicular phase FSH levels and may be responsible at least in part of the failure of the
other follicles to reach preovulatory status during any one cycle.

Estrogen dominant Microenvironment

 Follicular maturation requires a successful conversion from an “androgen-dominant”

microenvironment to an “estrogen-dominant” one.
 Androgens at low concentrations stimulate aromatization and contribute to Estrogen
production.
o Intrafollicular androgen levels will rise if aromatization in the granulosa cells lags behind
androgen production by the thecal layer.
 Androgens at higher concentrations are converted to the more potent 5α-androgens
(dihydrotestosterone). These inhibit aromatase activity, cannot be aromatized to estrogens and
inhibit FSH induction of LH-R expression on the granulosa cells.
 This model predicts that follicles that lack adequate FSH receptor and granulosa cell number will
remain primarly androgenic and will therefore become atretic. An increased androgen-to-
estrogen ratio is found in the follicular fluid of atretic follicles. High estrogen levels prevent
apoptosis.
 IGF-I also has apoptosis-suppressing activity. This is produced by granulosa cells. IGF-binding
proteins that are present in the follicular fluid of atretic follicles suppress its action. FSH has the
ability to stimulate IGF-I synthesis and suppress the synthesis of the IGF-binding proteins,
therefore preventing atresia.

ENDOMETRIUM: Histology

The endometrium consists of 2 layers

 Basalis layer. - lies against the myometrium. Does not change significantly across the menstrual
cycle. It serves as the reserve for endometrium regeneration following menstrual sloughing.
 Functionalis layer. - Opposed to the uterine lumen. It’s further subdivided into:
o Stratum compactum: a thin layer of gland necks and dense stroma
o Stratum spongiosum. - Underlying stratum. Contains gland and large amounts of loosely
organized stroma and interstitial tissue

MENSTRUAL CYCLE PHASES

Preovulatory phase
  During the end of a previous cycle, Estrogen, progesterone and inhibin levels decrease abruptly.
FSH circulating levels increase

Ovarian phase: Follicular phase

 This increase in FSH is responsible for the recruitment of the cohort of follicles that contains the
follicle destined for ovulation (the dominant follicle)
 During the mid-follicular phase, Follicles produce increased amounts of Estrogen and Inhibin,
resulting in a decline in FSH levels through a negative feedback. This drop in FSH is believe to
contribute to selection of the dominant follicle. The non-dominant follicles expressed a
decreased number of FSH receptors and therefore are unable to respond adequately to
declining FSH levels.
 During most follicular development, Granulosa cell responses to FSH stimulation include:
o Increase in granulosa cell number
o Increase in aromatase expression
o Expression of LH receptor (in the presence of estradiol)
 This occurs during the late follicular phase and makes the granulosa cells begin
to produce small amounts of Progesterone, which decreases granulosa cell
proliferation, slowing follicular growth.
 In women with waning ovarian function:
o The ovary may have a loss of Inhibin production, which produce an accelerated rise in
FSH levels relative to that of younger women at this point of the cycle. This results in a
more robust recruitment of follicles and may explain both the shortened follicular phase
observed in these older women and the increased incidence of spontaneous twinning.

Endometrial phase: Proliferative phase.

 After menses, the endometrium is 1-2 mm thick. Under the influence of estrogen, the glandular
and stromal cells of the functionalis layer proliferate rapidly following menses.
 As this phase progresses, the glands become more tortuous and cells lining the glandular lumen
undergo pseudostratification.
 The stroma remains compact.
 Endometrial thickness approximates 12 mm at the time of the LH surge and does not increase
significantly thereafter.

Ovulation

 Ovulation occurs randomly from either ovary. It does not alternate sides.
 Towards the end of the follicular phase:
o Estradiol levels increase dramatically. This triggers a change from negative to positive
feedback at both the hypothalamus and anterior pituitary gland to generate a surge in
LH levels. (Estradiol concentration of 200 pg/mL for 50 hours are necessary to initiate
this surge)
o Progesterone levels increase and generates a FSH level surge that occurs in tandem with
the LH surge. This increase may also augment the ability of Estradiol to trigger the LH
surge.
  The LH surge acts rapidly on both the Granulosa and Theca cells of the preovulatory follicle. Its
effects are:
o Termination of the genes involved in follicular expression and activation of the genes
necessary for ovulation and luteinization.
o Reentry of the oocyte into meiosis
o Expansion of the cumulus oophorus
o Synthesis of prostaglandins
o Luteinization of granulosa cells
 The mean duration of the LH surge is 48 hours. Ovulation occurs approximately 36-40 hours
after the onset of the surge.
 The abrupt termination of the LH surge is postulated to follow acutely increased steroid and
Inhibin secretion by the corpus luteum.
 The granulosa cells surrounding the oocyte, unlike mural granulosa cells, do not express LH
receptors or synthesize progesterone. These cumulus oophorus granulosa cells develop tight gap
junctions between themselves and with the oocyte. This mass that accompanies the ovulating
oocyte is believed to provide a rough surface and increased size to improve oocyte “pick-up” by
the tubal fimbria.
 Extrusion of the oocyte last only a few minutes. The exact mechanisms are poorly defined, but
are not due to an increase in follicular pressure.
o Proteolytic enzymes (Plasmin, Collagenase) are present in the follicle, which suggests
that these enzymes are responsible for follicular wall thinning.
o The preovulatory gonadotropin surge stimulates expression of tissue plasminogen
activator by the Theca and Granulosa cells, decreases expression of plasminogen
inhibitor and increase prostaglandin concentration in the follicular fluid. The latter may
stimulate smooth muscle contraction in the ovary, contributing to ovulation.

Postovulatory phase

Ovarian phase: Luteal phase

 Luteinization: Occurs following ovulation. The remaining follicular cells differentiated into the
corpus luteum (yellow body). This process requires LH stimulation and includes both
morphologic and functional changes.
o Granulosa cells: proliferate and undergo hypertrophy to form the granulosa-lutein cells
o Theca cells: proliferate and undergo hypertrophy to form the smaller theca-lutein cells
 During the Corpus luteum formation, the basement membrane that separates the granulosa
cells from the theca cells degenerates and allows vascularization of previously avascular
granulosa cells
o 2nd day after ovulation: capillary invasion beings
o 4th day after ovulation: capillaries reach the center of the corpus luteum
 The increase in perfusion provides these luteal cells with access to circulating LDL, which
provides the precursor cholesterol for steroid biosynthesis. This marked increase blood supply
can have clinical implications.
 Adequate steroidogenesis in the Corpus luteum depend on:
o LH levels
 o LH receptors on luteal cells (critical the LH receptor expression on granulosa cells during
the follicular phase)
o Suficient number of luteal cells
 Luteal function is also influence gonadotropin levels from the preceding follicular phase.
o A reduction in LH or FSH secretion is correlated with poor luteal function:
o Lack of FSH → ↓ total number of granulosa cells → suboptimal cycles with decreased
number of FSH-induced LH-R → less response to LH stimulation
 The luteal phase is considered Progesterone dominant. The follicular phase is considered
Estrogen dominant
 The Corpus luteum is the most active steroidogenic tissue in the body, given its increased
vascularization, cellular hypertrophy and increased number of intracellular organelles.
 At the midluteal phase:
o Maximal production of progesterone (40 mg of progesterone per day)
 Ovulation is assumed to occur if the progesterone level exceeds 3 ng/mL on
cycle day 21.
o Maximum levels of Estradiol are observed.
 Estradiol levels drop transiently after the LH surge (from direct inhibition of
granulosa cells growth by increasing progesterone levels)
 The corpus luteum produces large quantities of inhibin A that coincides with a decrease in
circulating FSH levels in the luteal phase.
o If Inhibin A levels decline at the end of the luteal phase, FSH levels rise once more to
begin selection of an oocyte cohort for the next menstrual cycle.
 If pregnancy does not occur, the corpus luteum regresses through a process called Luteolysis.
o Luteal regression is presumed to be tightly regulated as luteal cycle length varies
minimally among women.
o Following Luteolysis, the blood supply to the corpus luteum diminishes, progesterone
and estrogen secretion drop precipitously, luteal cells undergo apoptosis and become
fibrotic, creating the Corpus albicans (white body)
 If pregnancy occurs, hCG produced by the early gestation “rescues” the corpus luteum from
atresia by biding to and activating the LH-R on luteal cells (LH/CG receptor)
 hCG stimulation of corpus luteum steroidogenesis maintains endometrial stability until placental
steroid production is adequate to assume this function later in the first trimester

Endometrial phase: Secretory phase.

 Glycogen-rich subnuclear vacuoles appear in cells lining the glands. Under further stimulation by
progesterone, these vacuoles move from the glandular cells’ base tower their lumen and expel
their contents. This process peaks on approximately postovulatory day 6, coinciding with the
day of implantation
 Through the luteal phase, glands become increasingly tortuous, the stroma become more
edematous, the spiral arteries (feed the endometrium) increase their number and coiling.
 If a blastocyst does not implant and the corpus luteum is not maintained by the placental hCG:
o Progesterone levels drop
o Endometrial glands begin to collapse
 o Polymorphonuclear leukocytes and monocytes from nearby vessels infiltrate the
endometrium.
o The spiral arteries constrict, leading to local ischemia
o Lysosomes release proteolytic enzymes that accelerate tissue destruction.
o Prostaglandins particularly PG F2α are present in the endometrium and likely contribute
to arteriolar vasospasm. PG F2α also induces myometrial contractions, which may aid In
expelling the endometrial tissue
 The entire endometrial functionalis layer is thought to exfoliate with menses, leaving only the
basalis layer to provide cells or endometrial regeneration. But, the amount of tissue shed from
different levels of the endometrium varies widely
 Following menses, reepithelialization of the desquamated endometrium is initiated within 2-3
days after the onset of menses and completed within 48 hours

Regulation of endometrial function

Tissue degradation and hemorrhage

 Within the endometrium, numerous proteins maintain a balance between tissue integrity and
the localized destruction required for menstrual sloughing or for trophoblast invading during
implantation
 Cytokines, growth factors and steroid hormones are believe to regulate the genes encoding
these tissue proteins.
 Tissue factor: a membrane-associated protein. Activates the coagulation cascade upon contact
with blood
 Urokinase + Tissue plasminogen activator (TPA) increase the conversion to plasminogen to
plasmin to active tissue breakdown. TPA es blocked by plasminogen activator inhibitor 1,
present in endometrial stroma
 Matrix metalloproteinases (MMPs): an enzyme family with overlapping substrate specificities or
collagens and other extracellular matrix components. The composition of MMPs varies within
different endometrial tissue and during the menstrual cycle. Endogenous MMPs inhibitors are
increased premenstrual and limit MMP degradative activity.

Vasoconstriction

 Vasoconstriction produces ischemia, endometrial damage and subsequent menstrual sloughing.

 Within the endometrium, epithelial and stromal cells secrete Endothelin-1, a potent
vasoconstrictor.
 Enkephalinase.- endothelin-degrading enzyme expressed at its highest levels in the midsecretory
endometrium. However, during the luteal phase, the drop in serum progesterone, leads to loss
of enkephalinase expression. This permits increased endothelin activity promoting a physiologic
environment amenable to vasoconstriction.

Myometrial contractions

 Control blood loss by compressing endometrial vasculature and expelling menstrual discharge
  A fall in serum Progesterone decreases an enzyme that degrades prostaglandins, resulting in
increases in PG F2α activity in the myometrium and triggers myometrial contractions.

Estrogens and Progestins

 Their receptors in the endometrium is highly regulated across the menstrual cycle, providing
additional mechanisms for controlling steroid effects on endometrium development and
function.
 Estrogen receptor
o Expressed in the nuclei of epithelial, stromal and myometrial cells
o Concentrations peak during the proliferative phase
o During the luteal phase, a rising in progesterone levels decrease Estrogen-receptor
expression
 Progesterone receptor
o Peak at midcycle in response to rising Estrogen levels
o By midluteal phase, progesterone-receptor expression in the glandular epithelium is
nearly absent, although expression remains strong in the stromal compartment
 The proliferation and differentiation of the uterine epithelium is under control of Estradiol,
Progesterone and various Growth factors
 Estrogen interacts directly with its Estrogen receptor, but can also indirectly induce various
growth factors that include IGF-1, Transforming growth factor α, Epidermal growth factor.
o In women receiving unopposed estrogen therapy, endometrial hyperplasia is observed.
 Progesterone effects on endometrium vary among endometrial layers.
o Critical for the conversion of the functionalis layer from a proliferative to a secretory
pattern.
o Promotes cellular proliferation within the basalis layer

Growth Factors and Cell Adhesion Molecules

 Growth factors and associated receptors act in the endometrium. Each has its own pattern of
expression.
 Cell adhesion molecules play an important role. These include:
o Integrins
o Cadherins
o Selectins
o Immunoglobulin superfamily
 Each has been implicated in endometrial regeneration and embryo implantation.

Implantation Window

 The embryo enters the uterine cavity 2-3 days after fertilization with implantation beginning
approximately 4 days later.
 Normal implantation and embryonic development require synchronous development of the
endometrium and the embryo
o The human blastocyst may have less stringent requirements for implantation than other
species as ectopic implantation occurs relatively frequently
 Uterine receptivity.- Temporal windows for endometrial maturation during which trophetoderm
attaches to endometrial epithelial cells with subsequent invasion into endometrial stroma
o The window for implantation in the human is relatively broad, extending from day 20-24
of the menstrual cycle.
o Precise determination of this temporal windows is critical since only those factors
expressed during this time act as direct functional mediators of uterine receptivity
o Is associated with loss of surface microvilli and ciliated cells, and with development of
cellular protusions called: Pinopods, on the apical surface of the endometrium
 Pinopod are considered importante morphologic marker of periimplantation
endometrium
 Pinopod formation is known to be highly progesterone dependent
o Various factors are believe to be necessary for uterine receptivity (cell adhesion
molecules, Ig, cytokines. Integrins have been studied, but not a single integrin molecule
has been determined to be critical marker for implantation window to date)
 Luteal phase defect: describes dyssynchrony between endometrial development and menstrual
cycle phase that leads to subsequent implantation failure and early pregnancy loss.
o Term currently of limited clinical use due to our inability to diagnose and treat this
disorder.
 Following implantation, the endometrium undergoes essential remodeling by invading
trophoblast.
 Maternal endocrine environment changes extensively because of altered maternal physiology
and contributions by the placenta and fetus.