Assessment of endometrial receptivity

Bruce A. Lessey, M.D., Ph.D.

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University Medical Group, Greenville
Hospital System, Greenville, South Carolina

Objective: To provide a focused review of the scientific literature pertaining to endometrial receptivity.
Design: Review of the literature and appraisal of relevant articles.
Setting: Academic teaching hospital.
Patient(s): Women with infertility.
Intervention(s): None.
Main Outcome Measure(s): Critical review of the literature.
Result(s): Although a consensus has been achieved regarding the existence of a temporally defined period during
which embryo attachment and invasion can occur (called the window of implantation), reliable methods to assess
receptivity have not been established or adequately validated. In women with certain gynecologic disorders, in-
cluding endometriosis, tubal disease, and polycystic ovary syndrome, endometrial receptivity seems to be compro-
mised, leading to infertility and pregnancy loss. The establishment of reliable biomarkers for the detection of
defects in endometrial receptivity has been a long-sought goal that remains an elusive target. The validation of
endometrial biomarkers will require properly designed and implemented studies based on the recognition that
endometrial receptivity defects are not equally distributed in women with endometriosis or these other conditions.
Conclusion(s): Rapidly advancing technologies are bringing new biomarkers to the clinical arena that promise to
further reveal the complexities of the implantation process. (Fertil Steril
2011;96:5229. 2011 by American So-
ciety for Reproductive Medicine.)
Key Words: Endometrial receptivity, implantation, endometrium, endometriosis, infertility

The term endometrial receptivity refers to the ability of the uter-
ine lining to accept and accommodate a nascent embryo, resulting in
a successful pregnancy. This concept of a hostile vs. receptive endo-
metrium has evolved over many years from observations made by
the many researchers and clinicians who study implantation and/
or endometrial function. Endometrial receptivity is a useful model
to study the causes of unexplained infertility and pregnancy loss
as well. A related concept regarding a window of implantation
(WOI) that temporally frames the period of receptivity when endo-
metriumembryo interactions occur also focuses our collective un-
derstanding of pregnancy loss and infertility.
Progesterone is critical to endometrial receptivity, a lesson well
learned from the era of RU-486 (1), and functions to turn the
estrogen-primed endometrium into a secretory structure required
for embryo survival and implantation. The recognition that low
P might predispose to pregnancy loss was discussed as early as
1929 by Corner and Allen (2), with the naming of this concept
as luteal-phase deficiency some 20 years later by Georgianna-
Segar Jones in 1949 (3). Endometrial receptivity as an entity began
to take shape with the work of Rock and Bartlett (4), who later for-
malized a method of endometrial dating in the inaugural issue of
this journal in 1950 (5). Through careful examination of clinical
biopsy material, Noyes et al. (5) defined the histologic character-
istics of a secretory endometrium, describing the temporal re-
sponses to P. Most recently we have begun, in collaboration
with others, to dissect the molecular basis for these changes
(6, 7) and have used DNA microarray to understand the
Received July 11, 2011; accepted July 11, 2011.
B.A.L. has nothing to disclose.
Reprint requests: Bruce A. Lessey, M.D., Ph.D., Greenville Hospital
System, Center for Womens Medicine, 890 W. Faris Road, Ste. 470,
Greenville, SC 29605 (E-mail: blessey@ghs.org).
consequences of low P at the molecular level using in vivo
models of luteal-phase deficiency (8).
A literature search on endometrial receptivity yields more than
750 citations. One of the first of these appeared in the study by
Psychyos in 1973 (9), who later went on to investigate pinopodes
as biomarkers of the WOI in the human endometrium. The timing
of the WOI was further advanced by the early work of Hertig and
Rock (10), in a unique study of uterine samples in women attempt-
ing pregnancy before hysterectomy. By looking for and finding early
embryos in the process of attachment and invasion, this group de-
fined for the first time the earliest events in embryo implantation
in the human, finding that early attachment and invasion occurred
only after cycle day 19 of the menstrual cycle. The tissue collected
during this early study provided critical histologic material that later
became part of the Carnegie Series of implantation sites and formed
the basis for a staging system of implantation in the human (11).
Such studies were complemented by the later work of Hodgen
and coworkers in the primate endometrium (12) and Novot and col-
leagues using donor embryos in humans (1316), leading to the
conclusion that the WOI occupies a 4- to 5-day interval in the human
endometrial cycle, at the time when P reaches peak serum concen-
trations. Understanding when implantation occurs has led to the ap-
preciation of the importance of synchrony between embryo and
endometrium, as a critical component of successful pregnancy, first
in rodents (17) and later in humans (18). Our own work and the work
of others on endometrial steroid receptor changes (19, 20), as well as
the studies on endometrial integrin expression (21, 22), presaged the
placement of this WOI. The opening of the WOI on cycle days 19 to
20 is associated with loss of epithelial estrogen and P receptors in
normal women. This has now been shown to be a consistent
finding across many mammalian species studied, including mouse,
pig, horse, and nonhuman primate (2326). Spatial and temporal
changes in integrins in endometrium also exhibited alterations in

522 Fertility and Sterility Vol. 96, No. 3, September 2011 0015-0282/$36.00
Copyright 2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2011.07.1095
expression during the menstrual cycle that frames the WOI, as it is
now defined (27) (Fig. 1).
Understanding the regulation of endometrial receptivity in fertile
women has provided a better understanding of unexplained infertil-
ity and recurrent pregnancy loss (28). Through exploitation of mul-
tiple modalities of endometrial assessment, in both normal and
abnormal endometrium, methods such as thin-layer chromatogra-
phy of uterine secretions (2932), immunohistochemistry (33, 34),
differential display and reverse transcriptionpolymerase chain
reaction (35), DNA microarray (7, 3639), microRNA studies
(4042), and proteomic analysis (4345) have added to the
complexity of our understanding of endometrial receptivity.
The endometrium can be viewed as a gatekeeper, allowing em-
bryos to attach only under optimal conditions. The concept of a re-
ceptor-mediated mechanism of embryo attachment and invasion
provided a strategy for choosing biologically relevant biomarkers
of endometrial receptivity (4649). The use and selection of
appropriate biomarkers for any condition requires an
infrastructure of investigators in the basic, translational, and
clinical sciences, availability of technological resources, and
FIGURE 1
Increased expression of three integrins during the secretory phase seems to frame the window of implantation, with all three being
coexpressed only during days 2024 of an idealized 28-day cycle (27). Copyright American Society of Reproductive Medicine.
Lessey. Endometrial receptivity. Fertil Steril 2011.
Fertility and Sterility
biostatisticians and epidemiologists who can design studies to
validate their use. Although the perfect protein marker would be
functionally important to the process of implantation, consensus
as to which biomarkers to use for endometrial receptivity has not
been established. As recently reviewed (34), receptivity defects
have been noted in a variety of clinical disorders, including tubal dis-
ease (5052), endometriosis (5355), and polycystic ovary
syndrome (5659). With the number of potential candidates
generated through molecular techniques growing steadily (7, 38,
40, 41, 60), the focus on one over another biomarker has become
increasingly problematic. A conceptualized model of receptor/
biomarker candidates that have been suggested is shown in Figure 2.
The luminal epithelium of the endometrium is composed of
a sheet of specialized epithelial cells that are distinct from the glan-
dular cells and underlying stroma (61) and forms the primary barrier
to embryo attachment and invasion (6264). Microscopic
projections known as pinopodes (also called pinopods or
uterodomes) have been seriously considered as potential markers
of receptivity, with a putative evanescent expression pattern within
the 4- to 5-day period of receptivity. Evidence suggests that embryos
523
 FIGURE 2
Models of embryoendometrial attachment. From Donaghay and Lessey (34). Used with permission.
Lessey. Endometrial receptivity. Fertil Steril 2011.
are attracted to and/or preferentially interact with these structures
in vitro (65). Pinopodes were first named by Enders and Nelson
(drinking foot) as ultrastructural features in the rat uterus (66),
on the basis of their ability to take up ferritin from the uterine lumen.
In the human pinopodes were promoted by Psychyos and colleagues
(6771) and later by Nikas and colleagues (7276) as reliable
biomarkers of the WOI in humans, although this pinocytotic
function seems to be lacking. The quantitation of pinopodes
proved highly subjective, and an absence of these structures lead
to confusion, meaning that that they had already come and gone,
or conversely, that they had yet to appear. Most recent well-
designed studies have failed to show a reliable pattern for the expres-
sion of pinopodes (7779), and thus their significance as markers of
endometrial receptivity remains unproven.
Other luminal moieties include MUC1, which is a carbohydrate
glycoprotein that extends from the luminal surface and forms the
glycocalyx layer, as previously described (80). In the mouse (and
most mammals) MUC1 is considered a barrier to implantation and
disappears at the time of implantation (81, 82). MUC1 is
expressed throughout the WOI in humans, and unique
glycosylation patterns have been suggested as the explanation as
to how MUC1 might be involved in endometrial receptivity
(8385) and are actively studied today. Other luminal endometrial
biomarkers with a potential role in embryo attachment include
trophinin (49), L-selectin ligand (8689), and heparin-binding epi-
dermal growth factorlike growth factor (9093). None of these
biomarkers has been studied in sufficient detail to validate their
usefulness for the assessment of endometrial receptivity.
524 Lessey Endometrial receptivity
Infertility is a common problem encountered by one in five cou-
ples and is defined as the inability to conceive after 1 year of unpro-
tected intercourse. Nearly 8 million couples in the United States
experience infertility at any given time (94). Endometriosis is a ma-
jor cause of infertility, and although the prevalence is only 3%5%
of the general population, it accounts for up to 40% of infertility
cases (95). The yearly estimated cost for diagnosis and treatment
of endometriosis-associated infertility and pain, including loss of
productivity, is approximately $22 billion in the United States alone
(96). Endometriosis is likely the most common cause of endometrial
receptivity defects, especially in cases of minimal or mild disease
for which mechanical reasons do not explain the loss of fertility. It
is very important to note that only 50% of women with endometri-
osis are infertile (97). Any biomarkers of receptivity should be able
into account and address this type of heterogeneity.
Alterations in the eutopic endometrial phenotype in women with
endometriosis now point to an acquired P resistance, which in turn
alters endometrial function (98). Clinical instruments for the predic-
tion of fertility in women diagnosed with endometriosis have been
proposed (99). A search for suitable biomarkers that adequately de-
fine when endometrial receptivity is compromised is now part of
a comprehensive survey of research priorities for endometriosis
research (100).
One of the best-characterized endometrial biomarkers related to
infertility is the anb3 integrin (101). Integrins are a class of cell ad-
hesion molecules consisting of heterodimeric glyoproteins that are
anchored to the plasma membrane and serve multiple functions
within cells (102), including functions within the endometrium
Vol. 96, No. 3, September 2011
(103, 104). The anb3 integrin appears on the apex of luminal and
glandular cell surfaces, coinciding with the opening of the WOI.
The tight correlation between histology and anb3 integrin
expression has been demonstrated (21, 105), and its expression
persists into pregnancy with expansion to the decidua (21, 27).
The appearance of anb3 integrin on the apical surface is due to its
presence in the subnuclear secretory granules that typically
complete their transit by cycle day 19 to 20 (5). Expression of the
intact heterodimer is rate-limited by production of the b3 subunit,
which is regulated directly by the transcription factor HOXA10
(106). Both HOXA10 and anb3 have been shown to be significantly
reduced in the eutopic endometrium of women with mild but not
moderate or severe endometriosis (53, 107, 108). Similar to the
anb3 integrin, endometrial HOXA10 is reportedly reduced in both
adenomyosis (109) and polycystic ovary syndrome (58, 110), and
its loss in hydrosalpinges is restored by salpingectomy in
hydrosalpinges (52), similar to the anb3 integrin (50). Because
HOXA10 is hypermethylated in women with endometriosis, the
loss of anb3 integrin as a downstream measure of endometrial re-
ceptivity may be epigenetically defined in certain women with endo-
metriosis (55). In early studies that we performed, this integrin
seemed to address the issue of heterogeneity and endometriosis. In
women with endometriosis that expressed this integrin, pregnancy
rates were significantly better than in women with endometriosis
who were lacking this integrin (Fig. 3).
In vitro fertilization is a good model to study endometrial recep-
tivity (111). Both tubal disease with hydrosalpinges and endometri-
osis have been associated with decreased IVF success (112, 113),
and surgical correction of both is associated with an improvement
in subsequent pregnancy outcomes (114, 115). The anb3 integrin
has been looked at as a predictor of IVF success, but only
a limited number of studies have been published (116118).
Endometrial aromatase expression is an aberrant finding in
women with endometriosis (119) and is associated with poor IVF
pregnancy rates (120). Aromatase expression is associated with in-
FIGURE 3
The anb3 integrin in the endometrium of women with
endometriosis predicted success of pregnancy. Women with
endometriosis had a significantly better pregnancy rate when anb3
was present compared with women who lacked integrin
expression (P< .01).
Lessey. Endometrial receptivity. Fertil Steril 2011.
Fertility and Sterility
flammation, as seen with red lesions (milder forms) of endometriosis
(121), the same stage in which a loss of integrin expression has been
noted. Suppression of inflammation with prolonged GnRH analog
has also been shown to improve IVF outcomes when used before
IVF stimulation (122), perhaps functioning to reduce endometriosis
and improve endometrial receptivity.
Not all studies have found integrins to be useful biomarkers for
infertile women. Concerns have arisen from several key reports
(105, 123125). Hii and Rogers did not observe the now well-
documented cyclic expression of the anb3 integrin (105, 123), but
their negative finding was likely due to an artifact caused by the
inappropriate use of an antibody (LM609) in formalin-fixed rather
than cryopreserved tissues (126). A study by Creus et al. (105) failed
to demonstrate utility for prediction of endometriosis, on the basis of
a lack of endometrial integrin expression patterns. The patients in-
cluded in that study were different, however, using out-of-phase
and in-phase histology together, unlike the original study that only
included in-phase type II defects (53). In a more recent study, Sur-
rey et al. (124) studied the role of integrin testing for the prediction
of benefit for GnRH analog suppression in IVF patients with and
without endometriosis. The study could be criticized because of
the small sample size and lack of power to address their hypothesis,
but overall they did not see a significant reduction in IVF success
rates in integrin-negative patients.
Attention to proper study design will be required to address the
proper use of biomarkers for endometrial receptivity, especially
when studying endometriosis (127). Researchers must recognize
the fact that not all women with endometriosis are infertile (97),
and not all will lack expression of individual biomarkers. Not
all endometriosis is verifiable by the pathologist (128), making
it difficult to interpret the negative patient with visually sus-
pected endometriosis. In some studies the presence of endometri-
osis, including minimal or mild disease, seems to be ubiquitous
(129131), whereas some endometriosis might be barely visible
(132134). Studies that have investigated the role of
endometriosis on fertility sometimes include subjects who have
a prior diagnosis of endometriosis (135). Study inclusion of sub-
jects who have already undergone surgical diagnosis and treatment
of endometriosis is fundamentally flawed. Daya (136), who stud-
ied the relationship between pregnancy loss and endometriosis,
found an association only when patients were studied before lap-
aroscopy but not after the diagnosis had been made. Such funda-
mental flaws in study design have exacerbated the controversies
surrounding how mild endometriosis results in infertility or preg-
nancy loss (95).
A common theme that is emerging related to endometrial recep-
tivity is based on the inflammatory changes that occur in response to
infection, endometriosis, or tubal disease (137, 138). Endometriosis
is clearly an inflammatory condition (139, 140). Superficial lesions
seem to be more active than powder burn or scarred lesions at
producing inflammatory cytokines (107, 141144). Immune
mechanisms are the mediators of this inflammatory response and
can be divided into innate immunity, including monocytes,
macrophages, dendritic cells, neutrophils, basophils, and mast
cells, and natural killer cells from the lymphoid lineage. The
adaptive immune system includes the T and B cells, which require
cells of innate immunity for establishment of an immunologic
memory (145). Bone marrowderived cells traffic to endometrium
via steroid-regulated chemokine production (146, 147). Under
normal circumstances, dendritic cells and Treg cells increase at
the implantation site, along with uterine natural killer cells that
interact with the invading placental cells to both direct and limit
525
trophoblast invasion (148, 149). Bone marrowderived decidual
cells ultimately determine pregnancy outcomes (150159).
Because monocyte-derived leukocytes and uterine natural killer
cells constitute 20%40% of all endometrial cells, the types of cells
trafficking to the endometrium is likely to be critical to the establish-
ment of endometrial receptivity (148, 160, 161). A loss of function
due to inflammatory leukocytes could account for unexplained
infertility and recurrent pregnancy loss, especially in women with
minimal and mild endometriosis (151, 162167). Given its central
role in inflammation, the study of the immune system will likely
provide many new biomarkers and become fertile ground for
research into endometrial receptivity.
Future advances in the field of endometrial receptivity are dif-
ficult to predict, given rapid expansion of studies on implantation
and infertility. The fields of proteomics, epigenetics, DNA micro-
array for mRNA and microRNA, and the contributions based
on immunologic factors are merging and may some day provide
a theory of everything related to endometrial receptivity. The
technological advances have opened a floodgate of discovery
and provide a dazzling array of potential candidates for the assess-
ment of the endometrium. Complex and closely associated rela-
tionships between endocrinology and immunology provide the
potential for discovery of new biomarkers of endometrial receptiv-
ity (149, 163, 168172). Using DNA microarray as an example,
studies in normal (6, 7, 36) and abnormal endometrium provide
a growing list of potential biomarkers associated with the WOI
(37, 38, 173, 174). This net has been widened by the study of
microRNA species and DNA methylation differences (epigenetic
change), each with the potential to uniquely modulate
endometrial receptivity through alterations in gene expression
in women with infertility or endometriosis (4042, 55, 60, 175
177). Proteomics is an expanding field as well, furthering the
number of candidate biomarkers of endometrial receptivity
defects (44, 45, 178186).
In summary, the available biomarkers for the assessment of endo-
metrial receptivity are increasing exponentially, but validation of
these biomarkers has been limited. There is a paucity of studies
with adequate power and validity based on study design to help de-
termine which biomarkers have the greatest value and consistency.
Establishment of reliable biomarkers of endometrial receptivity
will likely require a re-examination of how these studies should
be performed and what patients should be included. Protocols to ad-
dress endometrial research remain a priority for those who diagnose
and treat unexplained infertility and pregnancy loss and will be in-
valuable in establishing, once and for all, a consensus as to what
an endometrial defect really means and how to best treat women
with reproductive failure resulting from a loss of endometrial
receptivity.

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