NEW_How to Improve Endometrium Receptivity (1).pptx

Oleh :
Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Sumatera Utara
How to Improve
Endometrium Receptivity?

01
For a successful pregnancy, the synchronic coordination between the embryonic
development and the endometrial status is crucial.
The endometrium is a hormonally regulated organ that is nonadhesive to embryos
throughout most of the menstrual cycle in humans.
A complex process that provides the embryo with the opportunity to attach, invade,
and develop, culminating in a new individual and continuation of the species.
The window of implantation extends 3-6 days within the secretory phase in most
normal women.
What is Endometrial Receptivity?

Physiology
Neykova K, Tosto V, Giardina I, Tsibizova V, Vakrilov G. Endometrial receptivity
and pregnancy outcome. J Matern Fetal Neonatal Med. 2022;35(13):2591-2605.
doi:10.1080/14767058.2020.1787977
02
Endometrial proliferation,
transformation and secretion
occur throughout a normal
menstrual cycle under the
influence of ovarian
hormones
Thus, the endometrium
gradually thickens and
changes its pattern

doi:10.1080/14767058.2020.1787977
03

Morphological and molecular
alterations during the “plasma
membrane transformation” in
human endometrium
Whitby S, Zhou W, Dimitriadis E. Alterations in Epithelial Cell Polarity During Endometrial
Receptivity: A Systematic Review. Front Endocrinol (Lausanne). 2020;11:596324. Published
2020 Oct 27. doi:10.3389/fendo.2020.596324
04

01
Attainment of endometrial receptivity is not an “all or none”, binary event, nor does
the analogy of a window suffice to account for clinical observations associated
with endometrial-related subfertility.
Degrees and types of abnormal receptivity lead to a range of reproductive
problems.
Endometrial Receptivity

Challenges
 Repeated implantation failures (RIF) are a constant
challenge in reproductive medicine with a significant impact
both on health providers and on infertile couples
Makrigiannakis A, Makrygiannakis F, Vrekoussis T. Approaches to Improve Endometrial
Receptivity in Case of Repeated Implantation Failures. Front Cell Dev Biol. 2021 Mar
16;9:613277. doi: 10.3389/fcell.2021.613277. PMID: 33796523; PMCID: PMC8007915.
06

Factors that reflect on
endometrial receptivity

Neykova K, Tosto V, Giardina I, Tsibizova V, Vakrilov G. Endometrial receptivity and
pregnancy outcome. J Matern Fetal Neonatal Med. 2022;35(13):2591-2605.
doi:10.1080/14767058.2020.1787977
Progesterone
08
Nowadays PG is considered the key hormone of pregnancy.
According to an international survey conducted in 2014, vaginal PG administration is
the most frequently used. (Vaisbuch et al, 2014).
However, luteal phase support (LPS) methods differ among doctors’, clinicians’, and
patients’ preference because there is no strong evidence of the superiority of one
method over another.

Progesterone
Liang, YX., Liu, L., Jin, ZY. et al. The high concentration of progesterone is harmful for
endometrial receptivity and decidualization. Sci Rep 8, 712 (2018).
https://doi.org/10.1038/s41598-017-18643-w.
09
Even if PG is recognized as “the main hormone of pregnancy”, Liang YX et al. observed
that high concentration of PG could negatively interfere with endometrial receptivity and
decidualization.
In their study, mouse models were used to examine effects of excessive PG levels on
embryo implantation and decidualization.
This study suggests a possible “side effect” of PG if not properly used, but further
studies are needed.

doi:10.1080/14767058.2020.1787977
Gonadotropine hormones
10
LH receptor expression at the endometrial site has been found to significantly increase
in the peri-implantation period. (Bonduelle, 1988)
Researchers reported a significant benefit from the addition of GnRH agonists to PG on
outcomes concerning live birth, successful clinical and ongoing pregnancy achievement
percentage. (Yu et al, 2016)

doi:10.1080/14767058.2020.1787977
Human Chorionic Gonadotropin (HCG)
• It has been discovered that hCG, derived from the blastocyst,
causes the secretion of specific pro-implantation factors.
11

Other Factors
The Preimplantation Factor (PIF) ELISA method is applied for its
detection.
doi:10.1080/14767058.2020.1787977
12
Genetic Factors
Other Factors

PCOS
Other molecular studies observed modified gene and protein expression profile in
predisposing conditions such as Polycystic Ovary Syndrome (PCOS). Overweight patients with PCOS showed
the lowest expression levels of HIF-1 alpha, VEGF and Glucose Transporter Protein-1 (GLUT-1). Thus, HIF-1
alpha in particular might be considered as a target for improving endometrial receptivity.
Wang et al (2021) found that Berberine could improve
ovulation in PCOS and the mechanism might be
associated with up-regulating LHCGR and CYP19A1.
Berberine could also improve endometrial receptivity
through down-regualting αvβ3 and LPAR3.
doi:10.1080/14767058.2020.1787977
13

PCOS
Yuan L, Wu H, Huang W, Bi Y, Qin A, Yang Y. The function of metformin in endometrial
receptivity (ER) of patients with polycyclic ovary syndrome (PCOS): a systematic review
and meta-analysis. Reprod Biol Endocrinol. 2021;19(1):89. Published 2021 Jun 14.
doi:10.1186/s12958-021-00772-7
Sixty-two eligible studies that included 6571 patients
were evaluated in this meta-analysis. Primary indicators
are EMT and endometrial aetery RI; secondary
indicators include the clinical pregnancy rate and
miscarriage rate.
Metformin significantly increased EMT (SMD = 2.04,
95% CI (0.96,3.12),P = 0.0002) and reduced
endometrial artery RI compared to the non-Met group
(SMD = - 2.83, 95% CI: (- 5.06, - 0.59), P = 0.01).
As expected, metformin also improved CPR and
reduced MR in PCOS patients as a result, clinical
pregnancy rate (risk ratio [RR] = 1.26, 95% CI: 1.11-
1.43, P = 0.0003), and miscarriage rate (RR = 0.73,
95% CI:0.58-0.91, P = 0.006).
Metformin may improve endometrial receptivity
(ER) in PCOS patients by increasing EMT and
reducing endometrial artery RI.
14

Dysbiotic Microbiome: A Novel Pathophysiologic Approach in RIF
doi:10.1080/14767058.2020.1787977
This study demonstrates the existence of an endometrial
microbiota that is highly stable during the acquisition of
endometrial receptivity. However, pathological modification of
its profile is associated with poor reproductive outcomes for in
vitro fertilization patients.
Twenty-six studies were included, 19 studying the vaginal
and seven investigating the uterine microbiome. Studies
using culture-based technologies found an abnormal
vaginal microbiome AVM was not associated with ART
outcome. However, studies using sequence-based
technologies found an abnormal vaginal microbiome had a
negative effect on ART.
15

• Global knowledge of endometrial receptivity grew up in recent years.
Improvements in genetics, new biomarkers, noninvasive methods, new
advanced techniques (Endometrial receptivity assay - the ERA system,
proteomic analysis) offer the possibility to evaluate the endometrial status and
to manage patients with infertility problems, especially women undergoing
assisted reproductive treatment.
doi:10.1080/14767058.2020.1787977
Recent Updates
16

doi:10.1080/14767058.2020.1787977
Predicting Endometrial Receptivity
17

Flow Cytometry
How to Improve Endometrium Receptivity?
doi:10.1080/14767058.2020.1787977
Conservative Methods
Several studies reported an impaired endometrium receptivity related to body mass
index (BMI).
Obesity is associated with endometrium receptivity. Thus nutritional supplementations
and physical exercises should positively induce a change in endometrium receptivity.
Smoking is another modifying factor that should interfere negatively with endometrial
receptivity.
18

Smoking
This study found that cigarette smoke contains
several thousand components (e.g. nicotine,
polycyclic aromatic hydrocarbons and cadmium)
with diverse effects. Each stage of reproductive
function, folliculogenesis, steroidogenesis,
embryo transport, endometrial receptivity,
endometrial angiogenesis, uterine blood flow
and uterine myometrium is a target for cigarette
smoke components.
The effects of cigarette smoke are dose-
dependent and are influenced by the presence of
other toxic substances and hormonal status.
Individual sensitivity, dose, time and type of
exposure also play a role in the impact of smoke
constituents on human fertility.
help to reduce cigarette smoking and provide a better
knowledge of the molecular mechanisms involved in
reproductive toxicology.
Further studies are necessary to better understand the
deleterious effects of cigarette smoke compounds on the
reproductive system in order to improve health care,
Dechanet C, Anahory T, Mathieu Daude JC, et al. Effects of cigarette smoking on
reproduction. Hum Reprod Update. 2011;17(1):76-95. doi:10.1093/humupd/dmq033 19

Flow Cytometry
doi:10.1080/14767058.2020.1787977
Could be corrected by the administration of vaginal PG
Establishing a therapeutic regimen with a vaginal estradiol and a PG
gel/suppositories could improve endometrial maturation for proper
implantation processes to occur.
20

Flow Cytometry
doi:10.1080/14767058.2020.1787977
Improvement of uterine blood flow
Low-dose aspirin (LDA) intake would block thromboxane A2, without any
effect on prostacyclin synthesis, which would lead to an increase in uterine
and ovarian artery blood flow.
L-arginine is a nitric oxide donor which could also eventually improve uterine
artery blood flow and thus, endometrial receptivity.
21

Acupuncture
doi:10.1080/14767058.2020.1787977
It is found very low to moderate level of evidence
that acupuncture may improve pregnancy rate
(RR = 1.23 95%CI[1.13, 1.34] P < 0.00001) and
embryo transfer rate (RR = 2.04 95%CI[1.13,
3.70] P = 0.02), increase trilinear endometrium
(RR = 1.47 95%CI [1.27, 1.70] P < 0.00001), and
thicken endometrium (SMD = 0.41 95% CI [0.11,
0.72] P = 0.008), compared with medication, sham
acupuncture or physiotherapy
The efficacy and safety of acupuncture on key outcomes
in women with low ER is statistically significant, but
the level of most evidence was very low or low.
22

ACUPUNCTURE
Forest Plot of
the pregnancy rate
Zhong Y, Zeng F, Liu W, Ma J, Guan Y, Song Y. Acupuncture in improving endometrial
receptivity: a systematic review and meta-analysis. BMC Complement Altern Med.
2019;19(1):61. Published 2019 Mar 13. doi:10.1186/s12906-019-2472-1
23

ACUPUNCTURE
Forest Plot of the
Endometrial patern
24

ACUPUNCTURE
Forest Plot of the
Endometrial thickness
25

ACUPUNCTURE
Forest Plot of the
Embryo transfer rate
26

ACUPUNCTURE
Forest Plot of the
Live birth rate
Forest Plot of the High-
quality embryo rate
27

Total: 80 patients of PCOS (by randomized)
- acupuncture plus medication group (40 cases)
- medication group (40 cases).
This study shows a remarkably increases the
levels of E2 and P in the serum, the endometrial
thickness and A-type rate. The therapeutic effects
of the combined intervention are remarkably better
than those of the simple application of clomiphene.
This combined intervention is safe and tolerable for
the adverse reactions. The effect mechanisms may
be related to the improvements of estrogen,
progestin and endometrial receptivity.
The combined intervention of electroacupuncture
and clomiphene achieves the definite effects of
ovulation and pregnancy promotion in PCOS.
Yu L, Cao L, Xie J, Shi Y. Zhongguo Zhen Jiu. 2018;38(3):263-268. doi:10.13703/j.0255-2930.2018.03.009
28

Total of 60 patients with PCOS of kidney
deficiency and blood stagnation pattern
were randomized into a combined
treatment group and a western medication
group, 30 cases in each one.
The therapeutic effect is better than the
simple western medication and its
mechanism is probably related to the
regulation of serum HOXA10 expression.
This study showed the combined treatment with acupuncture,
moxibustion and medication effectively improves endometrial
receptivity and uterine arterial flow in the patients with PCOS of kidney
deficiency and blood stagnation pattern and increases pregnancy rate.
Yu L, Cao L, Xie J, Shi Y. Zhongguo Zhen Jiu. 2018;38(3):263-268. doi:10.13703/j.0255-2930.2018.03.009
29

Endometrial Injury
Liang, YX., Liu, L., Jin, ZY. et al. The high concentration of progesterone is harmful for
endometrial receptivity and decidualization. Sci Rep 8, 712 (2018).
https://doi.org/10.1038/s41598-017-18643-w.
30
As far as basic science is concerned, endometrial injury has initially been proposed to induce an aseptic
inflammatory reaction possibly shifting the endometrial immune profile toward a Th2/M2 state (Granot et al.,
2012).
It was, thus, shown that endometrial injury may up-regulate the endometrial expression of several pro-
decidualization molecules, including MUC-1, crystalline aB, APOD, and PLA2 (Kalma et al., 2009).
MUC-1 is known to be up-regulated by progesterone affecting endometrial receptivity, acting at the same time
as an independent receptivity marker in case of RIF (Wu et al., 2018).
To the same direction, it has been shown that endometrial injury may induce uroplakin Ib expression, a molecule
up-regulated mainly during the window of implantation (Kalma et al., 2009).

Makrigiannakis A, Makrygiannakis F, Vrekoussis T. Approaches to Improve Endometrial Receptivity
in Case of Repeated Implantation Failures. Front Cell Dev Biol. 2021 Mar 16;9:613277.
doi: 10.3389/fcell.2021.613277. PMID: 33796523; PMCID: PMC8007915.
Endometrial Injury
31

Endometrial Injury
Continue…
32

Endometrial Injury
Continue…
33

Intrauterine Administration of Human Chorionic Gonadotropin (HCG)
34

Intrauterine Administration of
Peripheral Blood Mononuclear Cells (PBMC)
35

Intrauterine Administration of Platelet-Rich Plasma
36

Granulocyte Colony Stimulating Factor (G-CSF)
37

Atosiban
Atosiban is a receptor inhibitor of oxytocin and V1a vasopressin. Based on the observation that
embryo-transfer may trigger uterine contractions, which could be detrimental in embryonic
apposition, the first case report of a successful pregnancy after atosiban was published in 2007.
Pierzynski P, Reinheimer TM, Kuczynski W. Oxytocin antagonists may improve
infertility treatment. Fertil Steril. 2007;88(1):213.e19-213.e2.13E22.
doi:10.1016/j.fertnstert.2006.09.017
38

Atosiban
Pierzynski P, Reinheimer TM, Kuczynski W. Oxytocin antagonists may improve
infertility treatment. Fertil Steril. 2007;88(1):213.e19-213.e2.13E22.
doi:10.1016/j.fertnstert.2006.09.017
39

The concept of endometrial dysbiosis is emerging during the last 5 years. Several approaches have been
proposed as potentially effective in restoring normal endometrial microbiome
40
Efforts to Intervene in Case of Endometrial Dysbiosis
This review outlines the microbes (mostly bacteria)
identified in the endometrial microbiome studies, the
current treatments offered for bacterial dysbiosis in
the clinical setting, and the future possibilities such as
pro- and prebiotics and microbial transplants for
modifying uterine microbial composition.
Molina NM, Sola-Leyva A, Saez-Lara MJ, et al. New Opportunities for Endometrial Health by
Modifying Uterine Microbial Composition: Present or Future?. Biomolecules. 2020;10(4):593.
Published 2020 Apr 11. doi:10.3390/biom10040593

Bone Marrow Mesenchymal Stem Cells
This study found that BMSCs can migrate
to the endometrium and repair
damaged endometrium and improve
endometrium receptivity in a rat model.
Wang G, Ren C, Jiang J. Effects of bone marrow mesenchymal stem cells on repair
and receptivity of damaged endometrium in rats. J Obstet Gynaecol Res.
2021;47(9):3223-3231. doi:10.1111/jog.14888
41

A study reported that the water extract of Paeonia
lactiflora Pall. enhanced endometrial receptivity in
vitro and in vivo via induction of leukemia
inhibitory factor (LIF), an interleukin (IL)-6 family
cytokine.
Paenoia lactiflora
Park HR, Choi HJ, Kim BS, et al. Paeoniflorin Enhances Endometrial Receptivity
through Leukemia Inhibitory Factor. Biomolecules. 2021;11(3):439. Published
2021 Mar 16. doi:10.3390/biom11030439
42

Paenoia lactiflora
It is found that Paeoniflorin, a monoterpene glycoside which is the major active
compound of P. lactiflora, significantly improved the embryo implantation rate in
a murine model of mifepristone (RU486)-induced implantation failure.
In addition, paeoniflorin increased the adhesion of human trophectoderm-
derived JAr cells to endometrial Ishikawa cells through the expression of LIF
in vitro.
These results suggest that paeoniflorin might be a potent drug candidate for
the treatment of endometrial implantation failure by enhancing endometrial
receptivity.
2021 Mar 16. doi:10.3390/biom11030439
43

Paeoniflorin enhanced embryo implantation in mifepristone
(RU486)-induced implantation failure mouse model.
(A) Female mice were administered paeoniflorin (8 mg·kg−1·day−1) for 17 days.
Seven days after paeoniflorin administration, female mice were mated with
males. On day 4 from pregnancy, evidenced by vaginal plugs, female mice were
daily treated with RU (4 mg·kg−1·day−1) by subcutaneous injection for 4 days.
(B) Seven days after RU injections, mice were euthanized and the uteri were
excised. Representative image of an embryo-implanted uterus is shown.
Uterine tissue sections were stained with hematoxylin and eosin (H&E) and
histologically analyzed.
(C) The number of embryo implantation sites was counted and is expressed as
the mean ± standard error of the mean (SEM); *** p < 0.001 compared to
other groups; ns, no significance.
2021 Mar 16. doi:10.3390/biom11030439
44

Xiaoyao powder (XYP) is a traditional Chinese
medicine formula which has wide scope of indications
related to liver stagnation, reconcile qi and blood in
Traditional Chinese Medicine (TCM) syndrome.
The results demonstrated that XYP pretreatment could
improve endometrial receptivity, which leads to high
pregnancy rates. In the endometrium, XYP facilitated
angiogenesis by promoting tube formation.
Xiayao Powder
He M, Li L, Wei X, et al. Xiaoyao powder improves endometrial receptivity via VEGFR-2-
mediated angiogenesis through the activation of the JNK and P38 signaling pathways. 2022
Feb 10;284:114831]. J Ethnopharmacol. 2022;282:114580. doi:10.1016/j.jep.2021.114580
45

In the endometrium of women with recurrent
implantation failure and unexplained recurrent
miscarriage, the expression levels of homeobox A10 and
E-cadherin were positively correlated.
Homeobox A10 can bind to the E-cadherin promoter
region and directly regulate its expression, thereby
improving endometrial receptivity and subsequently
increasing the embryo adhesion and implantation.
Xiayao Powder
Bi Y, Huang W, Yuan L, et al. HOXA10 improves endometrial receptivity
by upregulating E-cadherin†. Biol Reprod. 2022;106(5):992-999.
doi:10.1093/biolre/ioac007
46

Operative Methods
Treatment of identified uterine pathology includes an eventual
laparoscopic treatment of endometriosis and/or hydrosalpings,
laparoscopic or hysteroscopy treatment of fibroids, hysteroscopy
treatment of intrauterine adhesions, uterine septum.
doi:10.1080/14767058.2020.1787977
47

This study showed a results in the patients of
hypdrosalphinx infertility after hysteroscopy and
laparoscopy, the combined therapy of heat sensitive
moxibustion and acupoint injection increases
endometrial thickness, reduces uterine arterial
resistance and improves endometrial receptivity.
. . .
Bi Y, Huang W, Yuan L, et al. HOXA10 improves endometrial receptivity
by upregulating E-cadherin†. Biol Reprod. 2022;106(5):992-999.
doi:10.1093/biolre/ioac007
48

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