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REVIEW
The Disorders of Endometrial Receptivity in PCOS and Its Mechanisms
Nan-Xing Jiang
1,2
&Xue-Lian Li
1,2
Received: 22 February 2021 /Accepted: 19 May 2021
#Society for Reproductive Investigation 2021
Abstract
Polycystic ovary syndrome (PCOS) is a mysterious and complicated endocrine disease with the combination of metabolic,
reproductive, psychological dysfunctions. Impaired endometrial receptivity and ovulation disorders/anovulation are both impor-
tant causes of PCOS-related infertility. However, change in endometrium has never received the same attention as ovulatory
dysfunction. Besides, putting emphasis on endometrial function may be more realistic for PCOS-related infertility, given the
wide use of assisted reproductive technology. The present review focuses on the disorders of endometrial receptivity of patients
with PCOS, summarizes the changes of the indicators of endometrial receptivity including leukemia inhibitory factor, homeobox
genes A, pinopodes, αvβ3-integrin, and intercellular junctions and also analyzes the possible mechanisms of decreased endo-
metrial receptivity and its relationship with the main endocrine and metabolic disorders of PCOS such as hyperandrogenism,
inflammation, insulin resistance, and obesity. Despite several biomarkers have been found to be associated with decreased
endometrial receptivity in PCOS, the clinical relevance of these findings still awaits future clarification.
Keywords Polycystic ovary syndrome (PCOS) .Endometrial receptivity .Insulin resistance .Infertility
Introduction
Polycystic ovary syndrome (PCOS), one of the most common
endocrine disorders in women, affects 8–13% of women of
reproductive age [1]. As one of the main features, infertility
affects 40% of women with PCOS [2].
Ovulation disorders/anovulation is an important cause of
PCOS-related infertility. With the development of technology,
nowadays we are able to obtain high-quality oocytes by con-
trolled ovarian hyperstimulation (COH), furthermore, the
quality of fertilized eggs are guaranteed by in vitro fertilization
(IVF). However, literatures have shown that when an ideal
blastocyst is transplanted in vitro, the success rate of trans-
plantation and live birth are lower among the women with
PCOS comparing to normal controls [3,4]. At the same time,
during assisted reproductive technology (ART), using the oo-
cytes donated by PCOS women will not lower the overall
success rate [5]. These make us consider the endometrial re-
ceptivity may be another important factor of PCOS-related
infertility. This review aims to illustrate the situation of endo-
metrial receptivity in women with PCOS and discuss the pos-
sible mechanisms.
“Endometrial receptivity”means the ability of endometri-
um to accept the implantation of embryo. Zygote is a seed and
endometrium is soil. The entrance of blastocysts into the en-
dometrium is called implantation. There are three processes
involved in the period of implantation: “location”,“adhesion”
and “invasion”. In four seasons of a year, only spring is suit-
able for sowing. Similarly, for women of childbearing age,
endometrium receptivity is present only for a very short time
in one menstrual cycle, typically occurring in the 22th to 24th
days of the cycle in the midsecretory phase [6]. This fleeting
moment is called “windows of implantation (WOI)”.
Endometrial receptivity mainly depends on the precise control
of estrogen (E2) and progesterone (P4) [7,8].
For infertile patients, there are no specific test to detect the
establishment of endometrial receptivity [9]. Methods like
hormone determination, ultrasonographic endometrial thick-
ness (EMT), spiral artery blood flow parameters, and uterine
artery blood flow parameters are proved to have some refer-
ence value [10], but without high accuracy [11]. Endometrial
receptivity array (ERA) is a unique innovative and objective
procedure for clinical endometrial evaluation [12]. It contains
*Xue-Lian Li
xllifc@fudan.edu.cn
1
Obstetrics and Gynecology Hospital, Fudan University,
Shanghai 200011, People’s Republic of China
2
Shanghai Key Laboratory of Female Reproductive Endocrine
Related Diseases, Obstetrics and Gynecology Hospital, Fudan
University, Shanghai 200011, People’sRepublicofChina
Reproductive Sciences
https://doi.org/10.1007/s43032-021-00629-9
a finite number of genes involved in endometrial receptivity,
thus avoiding the use of whole genome microarrays, which
cuts down on costs and simplifies the data analysis [12].
Further, ERA is more accurate than histologic dating and
is a reproducible method for the diagnosis of endometrial
dating and receptivity status [13]. However, as a new geno-
mic tool, ERA test has its limitations, it could not identify
the most appropriate time for embryo transfer or detect
uterine diseases affecting implantation. The invasive nature
of ERA is also its shortcoming that cannot be ignored [14].
New technologies may be necessary to assess the endome-
trial aspect of implantation. Nevertheless, the discovery of
some modern molecules has brought a glimmer of hope to
the evaluation of endometrial receptivity [15]. Nowadays,
some indicators have been found to be closely related to
endometrial receptivity, such as leukemia inhibitory factor
(LIF), homeobox genes A (HOXA), pinopodes, αvβ3-
integrin, and intercellular junctions [16,17]. The detailed
explanations are as follows.
I. LIF is a kind of cytokine secreted by endometrial glands
and belongs to IL-6 family. LIF plays an amazingly important
role in embryo implantation during WOI [18,19].
II. HOXA-gene is expressed in the epithelial and stromal
cells of uterus. Rats deficient in HOXA-10 and HOXA-11
showed embryo implantation disorders [20]. Similarly, re-
search found the downregulation of HOXA-10 mRNA and
protein expression levels in part of infertility patients [21].
III. Pinopodes are mushroom-resembled protrusions lo-
cated on luminal epithelium observed under electron micro-
scope. During WOI, the quantity and the density of
pinopodes increased rapidly, indicating the preparation for
embryo implantation [22].
IV. Integrin, a kind of adhesion molecule commonly found
on cell membrane, is a heterodimer composed of αand β
subunits. Integrins are present in both epithelial cells and stro-
mal cells in utero [23]. Integrin-ligand interactions enhance
the migration, adhesion, and invasion of trophoblasts [24].
Among them, the relationship between αvβ3-integrin and en-
dometrial receptivity is the most prominent.
V. Intercellular junctions between endometrial epithelial
cells not only constitute a complete epithelial barrier to main-
tain the integrity of the endometrium and prevent invasion of
external pathogenic factors, but also play an important role in
establishment of endometrial receptivity. The abnormal local-
ization or expression of intercellular junctions can lead to the
failure of endometrial decidualization and abnormal embryo
implantation [25,26].
These factors mentioned above are closely related. High
expression ofHOXA-10 was associated with the development
and increase of pinopodes. HOXA-genes also regulate β3-
integrin subunit in endometrium [27]. αvβ3-integrin, located
on pinopodes, participates in the crosstalk between embryo
and endometrium. Pinopodes can also release LIF-
containing secretory vesicles into uterine cavity [28], which
can increase the adhesion of trophoblast to endometrium by
upregulating the expression of αvβ3-integrin [29]. And these
indicators also have complicated changes in patients with
PCOS.
The Whole Picture of Endometrial Receptivity
in PCOS
More than 10 years ago, there was a controversy about wheth-
er PCOS had a negative effect on endometrial function [30].
Nowadays, with the gradual deepening of research, sufficient
evidence has proved that hormonal disturbances, as well as
metabolic changes in PCOS patients, can both influence the
endometrial receptivity [31,32].
At gene level, there is a differential gene expression in
endometrium of PCOS detected by microarray evaluation
[30,33]. It is noteworthy that the downregulated genes in
endometrium of PCOS are closely related to cell membrane,
extracellular matrix, cell adhesion and invasion, cytoskeleton,
and so on. What’s more, most of these genes are involved in
steroid hormone synthesis, inflammation, and oxidative stress,
which are indispensable for the establishment of endometrial
receptivity [33]. The proteome pattern of endometrium during
WOI in PCOS patients is significantly different with that in
normal female [34,35]. These differences in transcription,
post-transcriptional modification and translation are often re-
lated to metabolism, cell cycle, DNA repair, apoptosis, signal
transduction [33] and may consequently cause endometrial
hyperplasia, cancer, and impaired endometrial receptivity in
PCOS patients. However, specific mechanism is still un-
known. If we can pick out some proteins strongly associated
with endometrial receptivity from the proteome, it’spossible
to use them as drug targets for regulating suboptimal implan-
tation in PCOS. For instance, the protein complex consists of
osteopontin (OPN) and CD44 is an important adhesion mole-
cule in embryoimplantationthrough STAT1 and NF-κBpath-
ways [36]. Detection of CD44-OPN might be used to assess
the endometrial function of infertile patients in the future.
Recently, an article reviewed the importance of MicroRNAs
(miRNA) for female reproductive function [37]. At present,
human follicular fluids microarray profiling has proved the
significant difference of miRNA between PCOS patients and
normal female. Therefore, detection of miRNAs in peripheral
blood of PCOS patients may be used as one of the noninva-
sive methods to evaluate endometrial receptivity in the fu-
ture. NOTCH signaling pathway is widely present in verte-
brates and nonvertebrates and closely related to the differ-
entiation, as well as development of cells, tissues, and or-
gans. What’s more, NOTCH signaling pathway plays a
crucial role in embryo implantation. A study showed that
the expression of NOTCH3 was significantly increased in
Reprod. Sci.
PCOS women [38]. Changes in NOTCH signaling pathway
may be associated with decreased endometrial receptivity
in PCOS, but few studies have been done in this area up to
now [38,39].
The expression of LIF gene is obviously declined in en-
dometrial glandular epithelial cells in PCOS patients [40],
which is consistent with endometrial dysfunction and im-
plantation failure. LIF is regulated by estrogen and shows a
negative correlation, which is generally accepted at present
[41,42]. The precise regulation of sex hormones runs
through the whole pregnancy process, and the establish-
ment of endometrial receptivity is no exception. The regu-
lation of endometrial function by sex hormones may be
achieved through Wnt signaling pathway [43]. Generally
speaking, PCOS patients have upregulations of androgen
and estrogen, but a lower level of progesterone [44], which
may be a reason for the decrease of LIF in endometrium
with PCOS. However, there are few studies on how PCOS
affects endometrial receptivity through LIF-related path-
ways. The decrease of endometrial LIF in PCOS patients
may be result from inhibition of gene expression [40]. LIF
regulates endometrial receptivity via LIF/gp130-JAK/
STAT3 signaling pathway [45], but there is still a lack of
further researches on the upstream or downstream mole-
cules of this pathway. While the downstream of LIF-
STAT3 pathway may be through the transcription factor
named early growth response 1 (Egr1) [46]orkeyproteins
on endometrial lumen epithelial [45] to regulate endometri-
al receptivity. There is a research which holds the view that
it’s the adequate expression of LIFR, but not LIF, plays the
key role during the establishment of endometrial receptivity
[47]. But studies on LIFR and endometrial receptivity in
PCOS are still fruitless.
Endometrial biopsies obtained from PCOS women dem-
onstrated decreased HOXA10 mRNA [48].
Downregulation of HOXA-10 may affect endometrial re-
ceptivity by inhibiting the development of pinopodes [49].
Another article suggested that HOXA-10 is multifunctional
by regulating the proliferation, morphology and identity of
endometrial stromal cells and epithelium[50]. Laparoscopic
ovarian drilling (LOD), one of the treatments for PCOS, can
improve the levels of HOXA-10 and HOXA-11 mRNA in
endometrium of PCOS patients [51]. A previous study has
also found a decrease in αvβ3-integrin in endometrium of
PCOS patients [52],whichprobablycausedbythepersis-
tence of progesterone receptors (PR) in PCOS [53].
Recently, it has been proposed that epithelial β3-integrin
(EB3) can be used to evaluate endometrial receptivity [54].
Moreover, uterine fluid αvβ3-integrin has been proved as a
superior biomarker for embryo implantation [55].
Therefore, αvβ3-integrin may also be a potential target
molecule for evaluating the endometrial receptivity in
PCOS patients in the future [56].
The Effect of the Endocrine and Metabolic
Disorders of PCOS on Endometrial Receptivity
Hyperandrogenism (HA) and Endometrial Receptivity
in PCOS
Androgen regulates the endometrial receptivity by binding to
androgen receptors (AR), which is widely distributed in
glands, luminal epithelium, and stromal of uterus. The mech-
anisms of PCOS-related HA are as follows: PCOS ovary theca
cells expressed elevated 17α-hydroxylase/C17,20 lyase/17-
hydroxylase and 3β-HSD enzyme under pathologically stim-
ulated by hyperinsulinemia and overmuch LH, driving in-
creased androgen[57,58]. IR, pancreatic B cell dysfunction
and lipotoxicity [59,60] will reduce sex hormone-binding
globulin (SHBG), resulting in the soar of free testosterone
[61]. Meanwhile, androgen cannot convert to estrogen due
to the suppression of aromatase (CYP19), which is a key
enzyme for estrogen synthesis [62,63]. In turn, HA inhibits
the function of CYP19 as well, reinforcing a vicious cycle.
The latest research shows that the suppressing aromatase ex-
pression may connected to HUPCOS, a newfound lncRNA
[64]. PCOS-related HA also affects gene expression profiles,
including gene sets associated with autophagy, insulin signal-
ing, cell cycle, and glucose metabolism both in human endo-
metrium and during in vitro decidualization[65,66].
As a transcription factor, Wilms tumor suppressor gene
(WT1) expressed on endometrial stromal cells during WOI
[67,68]. Increased androgen receptors (AR) on endometrium
followed by the decline of WT1. Elevated Bcl2, which is one
of the targets of WT1, thereby blocks the cell cycle via p27
and impairs endometrial function. On the other hand, the sup-
pression of WT1 restrains epidermal growth factor receptor
(EGFR). The combination of EGFR and its ligand EGF is
bound up with the implantation of eggs during WOI. To
sum up, impaired endometrial receptivity of PCOS-related
infertility may closely relate to HA-WT1 pathway. Also, re-
covery of WT1 expression may be one of the reasons for the
effectiveness of antiandrogen therapy in PCOS [68–70].
Interestingly, contrast with endometrium, WT1 is
overexpressed in PCOS women’s ovaries, implicating the ef-
fects of the WT1 pathway are multifarious [71].
Both clinical and animal studies have shown that PCOS is
associated with the downregulation of HOXA-10 and HOXA-
11[40,48]. HOXA genes go hand in hand with steroid hor-
mones. In human endometrium, HOXA-10 increased in re-
sponse to elevated estrogen or progesterone. Androgen, how-
ever, has an opposite effect [48]. A dose-responsive decrease
of HOXA-10 mRNA level caused by testosterone was con-
firmed in vitro [48]. Similar phenomenon was observed in
extrauterine tissue. Testosterone at 10
–6
M can significantly
decrease HOXA10 protein in granulosa cells (GCs) [72].
LOD is helpful to improve the levels of HOXA-10 and
Reprod. Sci.
HOXA-11 mRNA in PCOS endometrium, which could be
explained by the remission of HA after surgery [51].
However, not all patients of PCOS have HA and therefore
there may exists more than one reasons responsible for the
altered expression of HOXA-gene.
In addition, the expression of various proteins in endome-
trial cells is androgen-dependent [73]. Ongoing HA may alter
the expression of proteins associated with endometrial devel-
opment and embryo implantation, which may be one of the
causes of decreased endometrial receptivity and miscarriage in
PCOS [73,74]. Elevated androgen may lead to a decrease the
level of CDKN2A in endometrium, thereby affecting the ac-
tivity of cyclin-dependent kinase (CDK). In vitro experiments
showed that the reduction of CDKN2a in Ishikawa cells re-
sulted in decreased migration, proliferation, invasion, and the
rate of Jar spheroid attachment to Ishikawa cell monolayer
[73]. L-selectin Ligand (MECA-79), an implantation protein
specifically expressed in WOI, reduced as well by the treat-
ment of testosterone [75]. HA causes the delayed
decidualization of endometrium, which is related to a
coregulator protein of AR named MAGEA-11. This may also
be a reason for PCOS-related infertility, but the specific mech-
anism is still unknown [70].
Testosterone can affect the expression of αvβ3-integrin, E-
Cadherin and Mucin-1[23]. It was reported that persistence of
PR in PCOS affects the expression of αvβ3-integrin [53]. The
downregulation of integrin after high-dose testosterone treat-
ment may be due to the counteraction of progesterone, which
causes the failure of maternal–fetal recognition, and then im-
pairs the establishment of pregnancy [23].
HA also affects intercellular junctions, thereby impairing
endometrial receptivity. Recently, an in-vivo study investigat-
ed the correlation between HA and intercellular junctions in
endometrium. The composition and proportion of claudin-4
and occludin determine the permeability and selectivity of
endometrial tight junction. HA can decrease the expression
of them, thus, impair endometrial tight junction [76].
Furthermore, in animal tests, the expression of connexin
26 improved, while connexin 43 were opposite after testos-
terone treatment [77]. Connexin 26 is acknowledged as a
marker of endometrial rejection. As for connexin 43, we
don't know yet if we can consider it as a marker of endo-
metrial receptivity from the evidence we have now. It has
been proved that HA can affect the intercellular junctions of
endometrium, thus affecting endometrial function and em-
bryo adhesion, which may be one of the reasons for the
decreased endometrial receptivity in PCOS patients.
However, these experiments have limitations. PCOS, a syn-
drome with multiple pathological features, is known for its
complexity and mystery. However, these experiments took
androgen as a single variable. No researches related to en-
dometrial intercellular junctions under complete PCOS
conditions have been published so far.
What's more, HA and IR can cause endometrial disorder of
oxidation and antioxidation by changing mitochondrial func-
tion [78]. The link between excessive ROS and PCOS has
been proved[79].
All in all, due to its complexity, follow-up studies are still
needed to figure out the relevance of HA and endometrial
receptivity of PCOS patients.
Inflammation and Endometrial Receptivity in PCOS
The whole process of pregnancy requires the precise regula-
tion of immune cells and cytokines, including embryo implan-
tation. Immune cells, especially uterine NK cells, regulatory T
cells (Treg), macrophages and dendritic cells (DC), play a key
role in inducing immune tolerance of blastocysts [80–82].
Excessive inflammation exists in certain diseases like PCOS,
endometriosis and therefore resulting in adverse pregnancy
outcomes. Some of the cytokines involved in the inflammato-
ry response are secreted by endometrial cells, while others are
secreted by immune cells recruited into uterus through blood
vessels. The whole process is regulated by E2 and P4 under
physiological conditions. The concentration gradient of cyto-
kines on endometrium guides the fertilized egg to a suitable
site for implantation [80,81,83]. Disorder of inflammatory
mediators can cause implantation failure and abnormal pla-
centa formation in mice and human [84].
Recent studies have found that miRNAs have a certain
effect on the occurrence and development of PCOS-related
inflammation. miR-4651 may participate in the inflammatory
response through leukocyte transendothelial migration by reg-
ulating target genes [85]. The expression of MiR-146a and
MiR-223 were significantly decreased in infertile women with
metabolic syndrome (MS). MiR-146a inhibits IRAK1-
TRAF6-NF-κB pathway and the downregulation of MiR-
146a is responsible for increased proinflammatory cytokine
and inflammatory response. The decreased expression of
miR-223 was related to the production of IL-1βand IL-
6[86]. Microarray profiling has shown that miRNA expres-
sion in PCOS patients is different from that in normal women
[37]. Detecting inflammation state in endometrium via
miRNA level to evaluate endometrial receptivity in PCOS
may be one of the future directions.
Chronic inflammation of PCOS is systemic. Higher levels
of serum inflammatory markers including IL-6, IL-16, IL-18,
TNF-α, and CRP are existing in PCOS [87–90]. Similarly,
low-grade chronic inflammation can also be detected in endo-
metrium [87]. Besides, it should be noted that whatever way
weight goes, inflammation shows in PCOS. Obesity is just an
aggravating factor.
The changes of implantation environment caused by in-
flammatory mediators may be a reason for impaired endome-
trial receptivity in PCOS patients. Piltonen et al. [84]pointed
out that the levels of IL-6, IL-8, monocyte chemoattractant
Reprod. Sci.
protein-1 (MCP-1), granulocyte-macrophage colony-stimulat-
ing factor (GM-CSF), and RANTES are markedly elevated in
undecidualized endometrial stromal fibroblasts (eSF) of
PCOS women. The disordered chronic inflammatory state of
PCOS women is also reflected in the downregulation of some
key cytokines. In an animal test [91], the expression of IL-1 of
PCOS group was significantly downregulated, accompanied
with declined thickness of endometrium. Stanniocalcin-1
(STC-1), a protective factor that reduce inflammatory stress,
is coexpressed with endometrial receptivity markers. The ex-
pression of STC-1 altered in PCOS patients, leading to a lack
of rescue mechanism in endometrium when faced with in-
flammatory stress. In addition, lifestyle changes cannot recov-
er STC-1 expression. Since STC-1 knockout mice has been
shown to be fertile, so it probably not a necessary factor for
implantation, but it’s dysfunction may, to some extent, worsen
the endometrial implantation microenvironment [92]. A study
analyzed the relationship between inflammatory chemokine
named fractalkine (FKN) and PCOS. PCOS patients have
higher circulating FKN levels than controls, and FKN level
is positively correlated with BMI, IR, inflammatory marker
CRP and total testosterone [93]. That is to say, FKN may
plays an important role in the intricated pathophysiology of
PCOS. Some inflammatory factors have been shown to be
associated with the expression of HOXA-gene, but the mech-
anism remains to be further investigated [94,95].
In recent years, researches on advanced glycation end
Products (AGEs) have received increasing attention. AGEs
are the end product of a nonenzymatic glycosylation reaction
(Maillard reaction) [96,97]. The accumulation of AGEs has
been confirmed to be closely related to many diseases, such as
diabetes and cardiovascular disease [98–100]. In this section,
we mainly describe the potential link among AGEs, inflam-
mation and decreased endometrial receptivity in PCOS.
AGEs act by binding to the membrane receptor (RAGEs).
AGE-RAGE combination activates a complex set of signaling
pathways so as to promoting downstream proinflammatory
signals including chemokines and cytokines [101]. There is
another soluble receptor called sRAGE, the product of both
splicing of RAGE-gene and cleavage of membrane-bound
RAGE by proteases belonging to the zinc-dependent
metzincin family of metalloproteases [102]. sRAGE compet-
itively binds to AGEs, thereby inhibiting the downstream pro-
inflammatory signals aroused by AGEs-RAGE combination.
Hence sRAGE is generally considered to be a protective
antiinflammatory receptor [100,103]. AGE-RAGE binding
leads to oxidative stress and inflammation in cells. As a pro-
tective factor, sRAGE can reduce inflammation level in PCOS
patients, which has been confirmed in human follicular cells
[100,103]. However, no article targeting to endometrium was
found. The significant difference in pregnancy outcome ob-
served in obese women probably due in part to elevated AGEs
in endometrium and the resulting inflammation [104]. The
influence of AGEs on VEGF has been detected in retinal
pigment epithelium [105]. Elevated AGEs have also been
demonstrated to cause damage to endothelial cell in arterio-
sclerosis of PCOS. And AGEs are related to reproductive
dysfunction in PCOS patients [100]. VEGF is an important
marker of endometrial receptivity, which is closely bond to
endometrial function and involved in placenta formation [91].
Endothelial injury impairs the physiological function of endo-
metrium as well. Unfortunately, there are few studies concen-
trating to the relationship between AGEs and endometrial re-
ceptivity of PCOS by far.
Insulin Resistance (IR) and Endometrial Receptivity in
PCOS
IR refers to the complicated pathological state of inadequate
response to insulin. Insulin -insulin receptor (INSR) binding
regulates glucose and lipid metabolism mainly through PI3-K
and Akt/PKB pathway. GLUT4 is a kind of insulin-
responsive glucose transporter. GLUT4 is transferred from
intracellular vesicles to plasma membrane so as to realize the
uptake of glucose. The activation of PI3-K and AKT/PKB
pathway also leads to serine phosphorylation of GSK3 to pro-
motes glycogen synthesis. Dysfunction of any link in insulin
metabolic pathway will lead to IR. [106–108]
Appropriate glucose metabolism is a key factor for embryo
implantation. Studies have shown that the oocytes from PCOS
patients with IR, neither its development or quality was affect-
ed after invitro culture. Unfortunately, the pregnancy rate was
significantly declined, which suggests that the foundation of
declined pregnancy rate caused by IR is the damage of endo-
metrium function and the obstacle of embryo implantation.
[108,109]
About 50–70% of PCOS patients have IR and concomitant
hyperinsulinemia [110]. There are multiple reasons for PCOS-
related IR, including HA, obesity, and inflammation.
Furthermore, these factors do not work alone but jointly form
an intricate network. PCOS women are prone to obesity, over-
much adipose tissue can affect insulinsensitivity.The death of
hypertrophic adipocytes activates IR and HA through inflam-
mation [111]. In human endometrial stromal cells, overload
TNF-αhas a negative effect on insulin sensitivity by reducing
adiponectin signal and blocking the transport of GLUT-4 to
membrane, resulting in abnormal energy metabolism [112,
113], which may be one of the reasons for impaired endome-
trial receptivity in PCOS. Meanwhile, excessive IL-6 reduces
the activation of IRS1 and AKT. When obesity and PCOS are
present, the destruction of insulin signaling is intensified
[114]. Besides, a research found that decreased oxidation of
cortisol might contribute to endometrial IR by inhibiting insu-
lin signaling pathway via induction of PTEN expression in
endometrial epithelial cells of PCOS women [108]. Besides,
HA aggravates IR as well [110]. In addition, sympathetic
Reprod. Sci.
nervous system (SNS) dysfunction is involved in the occur-
rence of IR. It was observed that the activation of SNS pro-
motes IR through increased lipolysis and inflammatory cas-
cades of P53 activation in adipose tissue in animal models of
heart failure [115]. Increased SNS activity can also be detected
in patients with PCOS because of inflammation. Which sug-
gests that low-grade inflammation in PCOS may contribute to
IR by mediating SNS dysfunction [110].
AGEs cause IR by affecting the insulin-mediated PI3K/
AKT signaling pathway [97]. AGEs inhibit insulin production
in pancreatic βcells and prevent membrane translocation of
GLUT4. However, these researches are mostly based on he-
patocytes and granulosa cells [98,116], studies on endometri-
um are still lacking.
It was known that PCOS affects glucose and energy me-
tabolism in endometrium by reducing GLUT4 expression,
so as to generate impaired endometrial receptivity [108].
However, a recent paper cast doubt on that point, the study
found that GLUT4 mRNA was not detected in the endome-
trium of PCOS or control group at all [66]. Therefore, the
link between PCOS-related IR and impaired endometrial
receptivity is still controversial and needs further studies
[66,108].
Obesity and Endometrial Receptivity in PCOS
Obesity is related to the above-mentioned pathophysiological
phenomena, such as HA, IR, low-grade chronic inflammation,
and excessive accumulation of AGEs [117]. Moreover, previ-
ous studies have shown that though some metabolic changes
caused by PCOS are independent of obesity, obesity undoubt-
edly an aggravating factor in metabolic disorders [117,118].
The influence of obesity, especially central obesity, on endo-
metrial receptivity of PCOS women cannot be ignored.
During WOI, obese women present significantly different en-
dometrial gene expression from the control group, which is
more obvious when PCOS or infertility is associated [119,
120].
In PCOS patients, there is a vicious circle between obesity
and other metabolic disturbances, thereby weakening the
function of endometrium (Fig. 1). Obesity exacerbates low-
grade chronic inflammation [121] and causes a drop in serum
SHBG level [122], thus aggravating HA. In addition, obesity
promote IR and overaccumulation of AGEs [121,123,124].
At the same time, these metabolic changes make an impact on
the occurrence and aggravation of obesity among PCOS pa-
tients. For instance, HA and IR can inhibit lipolysis and pro-
mote fat formation [125]. Overload inflammatory adipokine
can increase fat production in turn [126]. Lifestyle changes
such as weight loss or exercise can help PCOS patients alle-
viate symptoms and restore endometrial function [121,122,
127,128].
The Current Therapy Methods
and Endometrial Receptivity in PCOS
The specific treatment of implantation disorder in PCOS is
still no consensus, but some therapy methods have been
proved to be effective for the recovery of endometrial function
in PCOS.
The effect of metformin on PCOS endometrium has
gradually attracted more attention. Metformin improves
the systemic and intrauterine environment of PCOS pa-
tients by reducing HA, IR, and LH [129]. And studies have
confirmed that metformin may downregulate the expres-
sion of miR-491-3p and miR-1910-3p, thereby increasing
the levels of HOXA-10 and β3-integrin [130]. Moreover,
metformin is conducive to reverse the abnormal transcrip-
tion of endometrial autophagy genes caused by HA in
PCOS patients [65]. Nonetheless, the role of metformin in
endometrial receptivity with PCOS is not entirely benefi-
cial. Metformin seems to have a tendency to delay histolog-
ical glandular maturation [131]. Moreover, it is dose-
dependent on the proliferation of endometrial stromal cells
[132]. Inappropriate use of metformin may be counterpro-
ductive, while the optimal effective concentration is still
wrapped in the veil of mystery.
HA can inhibit the proliferation of endometrial stromal
cells. Restoring androgen level to normal range is benefi-
cial to the recovery of endometrial function in PCOS pa-
tients [132]. After LOD surgery, the increased expression
of HOXA-gene in endometrium of PCOS patients may be
relatedtotheremissionofHA[51]. The antiandrogen drug
named flutamide is effective in improving decidualization
and angiogenesis in uterine [133]. LIF is a marker of endo-
metrial receptivity, but studies have shown that treatment
with LIF cannot improve the success rate of embryo im-
plantation in infertility patients [134]. Myo-inositol
(MYO), an insulin sensitizer, is helpful to improve IR in
PCOS.MYOmayimproveendometrialfunctioninPCOS
patients through the increase of AMPK activation.
Furthermore, compared with metformin, MYO has a better
tolerance by women [135].
AGE/sRAGE may be a potential biomarker and a
promising therapeutic target for PCOS. In a 1-year ran-
domized controlled trial [136], scholars found that diet
low in AGEs (L-AGE) do good for IR in obese people
with MS, which suggests that AGEs might have a nega-
tive effect on insulin metabolism. AGE level affected
decidualization and endoplasmic reticulum stress of endo-
metrial stromal cells, and significantly inhibited the adhe-
sionandinvasionofembryo[104].RegardingtoL-AGE
diet, it gives us a hint, whether it is MS, type-2 diabetes,
or PCOS, L-AGE diet may be an adjuvant treatment
worth trying. As for PCOS-related infertility, if purely
from the perspective of endometrial receptivity. L-AGE
Reprod. Sci.
diet is possible to increase insulin sensitivity, reduce in-
flammation level and androgen, thereby alleviating resis-
tance to embryo implantation [136]. Last but not least,
appropriate exercise and normal range of BMI is essential
to improve the endometrial receptivity for PCOS patients
[121,122,127,128].
Vicious circle
Vicious circle
HA
HA
Inflammation
Inflammation
IR
IR
•HA/IR/inflammation promotes fat
formation
Ref. [125, 126]
•Obesity exacerbates inflamma-
tion and IR
•Obesity aggravates HA by
reducing SHBG
Ref. [121-124]
f.
f.
INSR and SNS
dysfunction
Ref. [114]
e.
e.
Elevated TNF-α and
macrophages
Ref. [89, 112, 143]
a.
a.
•Reduction in SHBG
•Increase in LH secretion
•Affects P450c17 enzyme
Ref. [125, 139-141]
b.
b.
Hyperandrogenic women have
a higher risk of developing IR
Ref. [142]
d.
d.
HA causes fat cell
hypertrophy and
inflammation
Ref. [110]
c.
c.
Cytokines cause HA
by theca cells
Ref. [89]
Fig. 1 The interaction and
vicious cycle among metabolic
disorders of PCOS
Table 1 The key findings of PCOS-metabolic/hormonal disturbances and their association with endometrial receptivity
PCOS-metabolic/hormonal
disturbances
The influence on endometrial receptivity Ref.
Hyperandrogenism Decreases the expression of LIF gene through Wnt signaling pathway.
Affects the expression of HOXA-gene and αvβ3-integrin.
Inhibits the development of pinopodes by the down-regulation of HOXA-10.
Decreases endometrial tight junction and proportion of claudin-4 and occludin and improves the expression
of connexin 26.
Alters the expression of receptivity-related proteins, e.g., CDK signal pathway, MECA-79, and
MAGEA-11.
Impairs endometrial receptivity through HA-WT1 pathway.
[40,43]
[23,48,
72]
[49,75]
[76,77]
[70,73,
75]
[68]
Inflammation Some inflammatory factors are associated with the expression of HOXA-gene.
AGE-RAGE binding leads to oxidative stress and inflammation in cells, and impairs endometrial function by
VEGF.
Disorder of inflammatory mediators leads to impaired endometrial receptivity in PCOS.
[94,95]
[91,100]
[84,91]
Insulin resistance Causes endometrial disorder of oxidation and antioxidation by changing mitochondrial function.
PCOS affect glucose metabolism in endometrium by reducing GLUT4 expression.
[78]
[108]
Obesity During WOI, obese women present different endometrial gene expression from the control group, which is
more obvious when PCOS or infertility is associated.
There is a vicious circle between obesity and other PCOS-metabolic/hormonal disturbances. (Fig. 1)
[119,120]
[104,117,
118]
Reprod. Sci.
Conclusions and Prospects
In the present review, we discussed the factors related to
endometrial receptivity in PCOS. These factors also have
potential to be used as indicators for evaluating endometrial
receptivity in the future [15–17]. The decrease of endome-
trial receptivity is one of the most important causes of
PCOS-related infertility. Yet it has never received the same
attention as ovulatory dysfunction. Part of relevant patho-
physiological changes in PCOS has been confirmed to be
associated with decreased endometrial receptivity. The key
findings of PCOS-metabolic/hormonal disturbances and
their association with endometrial receptivity are shown
in Table 1. To date, however, little progress has been
achieved for clinical integration in terms of prognostic tests
and treatments for suboptimal endometrial receptivity. We
are still unable to evaluate endometrial receptivity for
PCOS patients in an effective and noninvasive manner
[9–11,14]. Regarding PCOS-related infertility, the specific
mechanism of endometrial receptivity changes still needs
further researches.
However, the veil of mist hiding the truth from view will
gradually fade away. Modern molecules have shown great
potential as biomarkers in diagnosis, prognosis, and also as
possible therapeutic targets in PCOS-related infertility.
Currently, endometrial dysfunction is the biggest obstacle to
the treatment of embryo implantation difficulties [137,138].
In contrast to endometrial biopsy, as a noninvasive, accurate
marker, systematic profiling of indicators of endometrial re-
ceptivity including LIF, HOXA, pinopodes, αvβ3-integrin,
and intercellular junctions is needed both to identify implan-
tation defects in PCOS women and to signal the optimal
timing for embryo transfer. In the future, further exploration
regarding endometrial receptivity in PCOS is bound to be
difficult but full of infinite hopes and expectations.
Acknowledgements The authors would like to thank the support from
Natural Science Foundation from Science and Technology Commission
of Shanghai Municipality.
Code availability Not applicable.
Funding This study was funded by Natural Science Foundation from
Science and Technology Commission of Shanghai Municipality (grant
no. 17ZR1403100 to Xue-Lian Li).
Data availability All data generated or analyzed during this study are
included in this published article and its supplementary information files.
Declarations
Ethics approval Not applicable.
Consent to participate Not applicable.
Consent for publication Not applicable.
Competing interests The authors declare that they have no competing
interests.
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