Middle East Fertility Society Journal 23 (2018) 1–7

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Middle East Fertility Society Journal

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Review

The thin endometrium in assisted reproductive technology: An ongoing

challenge
Maryam Eftekhar a, Nasim Tabibnejad a,⇑, Afsar Alsadat Tabatabaie b
a
Department of Obstetrics & Gynecology, Shahid Sadoughi University of Medical Science, Yazd, Iran
b
Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Science, Yazd, Iran

a r t i c l e i n f o a b s t r a c t

Article history: Thin endometrium is identified to adversely affect reproductive success rates after assisted reproductive
Received 3 December 2017 technology (ART). Several treatment modalities have been presented to patients with thin endometrium,
Accepted 15 December 2017 to improve endometrial thickness and the subsequent endometrial receptivity. These approaches com-
Available online 21 December 2017
prising hormonal management by estradiol, tamoxifen, human chorionic gonadotropin (hCG) and
gonadotropin-releasing hormone (GnRH) agonist, vasoactive agents such as aspirin, vitamin E, pentoxi-
Keywords: fylline, nitroglycerin and sildenafil, intra-uterine infusion of growth factor such as Granulocyte Colony
Thin endometrium
Stimulating Factor (G-CSF) and the latest application of platelet-rich plasma, electrical stimulation, regen-
ART
Treatment, endometrial receptivity
erative medicine and presentation of endometrial receptivity array. In spite of the large variety of treat-
ment, most of the choices achieve only minor modification in the endometrium thickness and have not
been validated so far. Treatment of thin endometrium remains a challenge and future enormous investi-
gations are required to further clarification and ideal management of patients with thin endometrium.
Ó 2017 Middle East Fertility Society. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Pathophysiology of thin endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Treatment of thin endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3.1. Estradiol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3.2. Human chorionic gonadotropin (hCG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3.3. Midluteal GnRH-agonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.4. Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.5. Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.6. Sildenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.7. Vitamin E and pentoxifylline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.8. Nitroglycerin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.9. Granulocyte colony stimulating factor (G-CSF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.10. Platelet-rich plasma (PRP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.11. Neuromuscular electrical stimulation (NMES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.12. Stem cell therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.13. Endometrial receptivity array (ERA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Peer review under responsibility of Middle East Fertility Society.

⇑ Corresponding author at: Yazd Reproductive Sciences Institute, Shahid
Sadoughi University of Medical Science, Bouali Ave, Safayieh, Yazd, Iran.
E-mail address: nasimtabibnejad@ssu.ac.ir (N. Tabibnejad).

https://doi.org/10.1016/j.mefs.2017.12.006
1110-5690/Ó 2017 Middle East Fertility Society. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2 M. Eftekhar et al. / Middle East Fertility Society Journal 23 (2018) 1–7

1. Introduction 3. Treatment of thin endometrium

Despite recent developments in assisted reproductive tech- Since a thin endometrium is a multifactorial condition, its man-
niques (ART), the implantation rates still remain relatively low. agement should be cause-related, with the aim of increasing
Successful implantation requires high quality embryo, receptive endometrial receptivity and simplifying implantation [30,31].
endometrium, and perfect embryo transfer technique [1]. The However, improving endometrial growth in patients with thin
receptive endometrium define as a healthy uterine milieu contain- endometrium is very challenging; several regimens have been
ing the transformation of endometrial cells into decidua cells tried in the literatures [21,29,30].
appropriate for implantation of blastocysts, and rapid growth of
placenta [2]. Therefore, endometrial assessment is routinely per-
3.1. Estradiol
formed during in vitro fertilization (IVF) and intracytoplasmic
sperm injection (ICSI). In addition endometrial thickness (EMT)
Infertile patients, who display inadequate endometrium thick-
have been considered as a marker of endometrium receptivity [3]
ness, will be initially treated with oral estradiol. As the endome-
and a prognostic factors for embryo transfers during IVF/ICSI treat-
trium is a hormone dependent tissue estrogen supports
ment [4,5]. It is known that appropriate endometrial thickness is
endometrial proliferation by causing spiral artery contraction and
essential for a successful pregnancy [6,7] and several studies have
decreasing oxygen tension in the functional layer, that simplifies
stated low pregnancy rates in the presence of thin endometrium
embryo implantation [32,33]. The best method for prescription of
[8–11]. The optimal endometrial thickness for conception remains
estradiol is oral administration, and there are no significant differ-
controversial among clinicians. EMT less than 7 mm on ultrasound
ences between micronized estradiol or estradiol valerate [34]. The
is generally considered sub-optimal for embryo transfer and is cor-
extended administration of estradiol valerate during controlled
related to a decreased probability of pregnancy. Thin endometrium
ovarian hyperstimulation (COH) cycles for 14–82 days, improve
remains a challenge in gynecology and reproductive science with
the mean endometrial thickness from 6.7 to 8.6 mm as well as sig-
only slight enhancements attained with the currently available
nificant increase of pregnancy rate (38.5 vs. 4.3%) [35]. Similarly a
treatment. In this review, we focus on developing and promising
case of repeated implantation failure due to unreceptive thin endo-
treatment options for refractory thin endometrium.
metrium received extended estrogen supplementation for an
extended period, using 16 mg/day of estradiol valerate from the
third day of her menstrual cycle for 9 days before COH. IVF in this
patient led to a twin pregnancy and delivery at term [36]. In con-
2. Pathophysiology of thin endometrium
trast Demir et al. reported that estradiol supplementation with
estradiol hemihydrate 4 mg/day started on the day of hCG among
It has been supposed that a thin endometrium is caused by a
women with thin endometrium undergoing ICSI, did not improve
diminished normal endometrial growth. However, little evidence
clinical pregnancy rate, implantation rate (16% vs. 10.4%), and
is presented with regards to reasons for impaired endometrial
endometrial thickness [37]. According to a meta-analysis results,
growth in patients with thin endometrium. Acute or chronic infec-
administration of pure ethinyl estradiol (EE) for treatment of thin
tion like genital tuberculosis may result in destruction of endome-
endometrium, increase the endometrial thickness in comparison
trium basal layer due to replacing healthy endometrium by fibroid
to patients whom used placebo. Moreover, the best result were
tissue after healing [12]. Iatrogenic thin endometrium can be
achieved while EE administration is starting on 7th–10th day of
occurred by surgical procedures such as repeated curettage,
menstrual cycle with the dose of 0.02–0.05 mg/day for 5 days
polypectomy, laparoscopic or hysteroscopic myomectomy as well
[38]. As the highest serum and endometrial level of estrogen occur
as immethodical drug usage such as clomiphene citrate [12]. It is
after vaginal administration, it is considered as the desirable route
also indicated that thin endometrium may be a result of individual
in cases that do not response to the other ways. Therefore, Cetin-
uterine structural pattern [13].
kaya and colleagues administered estrogen vaginally 25 mg daily
Angiogenesis plays a key role in different female reproductive
from 4th day of the cycle for 15 days in Clomiphene citrate induced
developments, including growth of dominant follicles, formation
cycle. They reported significant increase in endometrial thickness
of a corpus luteum, and endometrial pattern [14–18]. Endometrial
on the day of ovulation in estrogen + clomiphene citrate group
angiogenesis is vital for regeneration endometrium after menstru-
compare to the group where only Clomiphene citrate was used,
ation and to provide a vascularized receptive endometrium for
but there was no difference in pregnancy rate [39]. In the same
implantation [14,17]. The majority of studies has focused on vascu-
way another study compared oral and vaginal administration of
lar endothelial growth factor (VEGF) as a regulator for endometrial
estradiol among donor oocytes recipients. The results showed an
angiogenesis, and a number of works stated that VEGF is expressed
increase in endometrial thickness as well as ongoing pregnancy
differentially in the uterine with thin endometrium [17,19–21].
rate when vaginal estradiol administration extended to 4–6 weeks
Uterine blood flow is an essential marker regulating endometrial
in women who failed to achieve acceptable endometrial thickness
growth and is narrowly related to vascular development of the
after oral estradiol administration [40]. Oral estrogens were also
endometrium [22–25]. Recent improvements in ultrasonography
used for endometrium preparation in FET, where prior IVF failure
have provided new opportunities for noninvasive evaluation of
was believed to be due to thin endometrium. Jimenez and col-
endometrial perfusion. A significant reduced pregnancy rate in
leagues administered oral estradiol 2 mg three times a day from
IVF-ET patients with low uterine blood flow, displayed a close rela-
day 1st for 12 days. They stated satisfactory development of endo-
tionship between uterine blood flow and uterine receptivity
metrium in 67% patients [41].
[26,27]. Asherman’s syndrome is one of the causes of thin endome-
trium. Transvaginal ultrasonography usually reveals minimal
endometrial thickness in this patients [28]. Impaired uterine perfu- 3.2. Human chorionic gonadotropin (hCG)
sion is the reason for atrophy of the remaining endometrium due
to restricted exposure to circulating hormones. This syndrome hCG play a local paracrine role in the endometrium differentia-
may occur followed myometrial fibrosis that is remarkably tion and endometrial receptivity by regulating different cytokines
increased among women with intrauterine adhesions (IUAs) com- and growth factors [42,43]. Papanikolaou and colleagues recruited
pared to healthy controls [29]. seventeen infertile patients with the history of implantation fail-
 M. Eftekhar et al. / Middle East Fertility Society Journal 23 (2018) 1–7
ures and resistant thin endometrium. On day 8 or 9 of the estrogen
administration (8 mg daily), hCG injection was started subcuta-
neously by 150 IU daily for 7 days. After a week on hCG priming,
on the day 14 or 15 of cycle, the mean endometrial thickness
was improved by 0.8 mm. Such as 35.3% of the patients had more
than 20% development in their endometrial thickness after hCG
priming and 17% achieved an endometrial thickness more than
7 mm [44]. Likewise in a nonrandomized clinical trial the effect
of adding hCG to frozen thawed embryo transfer cycles with
history of thin endometrium was examined in 28 patients who
had two previous failed cycles because of thin endometrium.
150 IU hCG was administrated intramuscularly from the day 8 of
cycle until endometrial thickness reached at least 7 mm. The study
suggested that adding hCG to the conventional method is effective
and improved endometrial thickness and pregnancy outcomes
significantly [45].
3.3. Midluteal GnRH-agonist
According to the evidence that mid-luteal GnRH-agonist admin-
istration improve pregnancy rate, one hundred and twenty women
with thin endometrium undergoing IVF received either triptorelin
(0.1 mg) on the day of ovum pickup, day of embryo transfer and
three days afterward as case group, or placebo as controls. The
results indicated that treatment with GnRH-a increases the
implantation and pregnancy rate significantly as the same as E2,
progesterone levels and endometrial thickness [46].
3.4. Tamoxifen
Tamoxifen blocks the actions of estrogen and has a key role in
endocrine therapy for the treatment of estrogen receptor positive
breast cancer. Wang et al. compared reproductive outcome in ovar-
ian stimulation cycles using tamoxifen (40 mg/day from day 3 of
the menstrual cycle for 7 days) and clomiphene cycles (100 mg/day
for 5 days) in patients undergoing intrauterine insemination. It was
found that tamoxifen-treated patients have a significantly
increased endometrial thickness and pregnancy rate [47]. Simi-
larly, another study showed that switching CC to tamoxifen for
ovulation induction in women with adequate follicular recruit-
ment and thin endometrium improves endometrial thickness
[48]. Ke et al. evaluate the effect of tamoxifen on endometrial
thickness among patients with thin endometrium undergoing fro-
zen–thawed embryo transfer cycles. 226 women who had
endometrial thickness less than 7.5 mm in previous cycles were
recruited. Tamoxifen administration improves endometrial thick-
ness in patients after natural cycle as the same as hormone
replacement treatment and ovulation induction cycles during
FET. However, Patients with PCOS got the most advantage
from tamoxifen and achieve higher pregnancy outcomes [49].
3.5. Aspirin
The effect of low dose aspirin on pregnancy rate is still debated
in the literatures. Even though some studies reported the positive
impact of low dose aspirin on endometrial thickness, pattern, and
endometrial blood flow [50,51], others claimed that aspirin do not
increase success of implantation [25,52]. Hsieh et al. found signif-
icantly higher percentages of trilaminar endometrium (46.5% vs.
26.2%) and pregnancy rates (18.4% vs. 9.0%) following low-dose
aspirin (100 mg) therapy non-aspirin group [53]. In a systematic
review and meta-analysis the effect of low-dose aspirin on likeli-
hood of pregnancy was studied among women undergoing IVF/
ICSI. Clinical pregnancy rate per embryo transfer was similar
between patients who received low-dose aspirin and those who
used placebo or no treatment (RR 1.09, 95% CI 0.92–1.29). Further-
3
more, Clinical pregnancy per cycle, spontaneous abortion or ecto-
pic pregnancy per Clinical pregnancy and live birth rate per cycle
or embryo transfer were not significantly significant between the
mentioned groups [54]. On the basis of a Cochrane study, low-
dose aspirin has no substantial positive effect on pregnancy and
endometrial thickness [55].
3.6. Sildenafil
Sildenafil citrate -an inhibitor of cGMP specific phosphodi-
esterase type 5 (PDE5)- prevents the breakdown of cGMP and
increases the effect of nitric oxide on vascular smooth muscles.
Sildenafil citrate administration cause an improvement in uterine
blood flow and, in combination with estrogen, could lead to the
estrogen-induced proliferation of the endometrial lining [24]. The
expression of vascular endothelial growth factor (VEGF) and Tumor
suppressor factor (p53) genes are essential for breaking down the
endometrial cellular matrix, normalize cell growth, and induce
angiogenesis. These process are required for adequate endometrial
blood supply and consequent embryo implantation [56,57]. Silde-
nafil citrate causes significant increases in p53 activity and stimu-
lated angiogenic reactions with elevated VEGF [58,59]. It is showed
previously that vaginal sildenafil citrate is effective for the treat-
ment of women with repeated implantation failure and leads to
increase endometrial thickness and attaining pregnancy in women
with poor endometrial growth [60]. Takasaki et al. evaluated the
effect of sildenafil on improving radial arteries blood flow and
endometrial growth. Sildenafil citrate increased radial artery-
resistance index and endometrial thickness in 92% cases [61].
Recently Zinger et al. have reported two infertility patients with
Asherman’s syndrome with successful pregnancy after consuming
25 mg vaginal sildenafil citrate, four times a day for 6–14 days dur-
ing the first half of their cycle [62]. To evaluate the effects of silde-
nafil administration on the thickness of the endometrium and the
implantation rate, Dehghani-Firouzabadi and coworkers conducted
a randomized controlled trial. 80 patients who had a history of
poor endometrial response and frozen embryos included the study.
40 patients were given sildenafil citrate tablets (50 mg) daily in
addition to the estradiol and compared to 40 women who received
estradiol only. They concluded that the oral usage of sildenafil
citrate is a good approach to improve the endometrial receptivity
[60]. Likewise, a recent study examined the effect of adding silde-
nafil vaginal gel to CC in infertile women with thin endometrium
and previous CC failure (5 cycles). In the patients’ 6th cycle (CC
only), women sustained on CC 100 mg/day for 5 days. In the 7th
cycle, women administered usual dose of CC supplemented in con-
junction with sildenafil vaginal gel (5 gm, containing 50 mg silde-
nafil) twice daily from day 8 to day of HCG administration. The
finding indicated that sildenafil vaginal gel considerably increased
endometrial thickness and uterine blood flow, and may improve
pregnancy rate [63].
3.7. Vitamin E and pentoxifylline
The combination of pentoxifylline (PTX) as a derivative of
methylxanthine that induce vasodilatation and vitamin E as an
antioxidant was used for treatment of thin endometrium. This
combination was given to oocyte recipients with inadequate
endometrial thickness after vaginal E2 administraion. This method
results in significantly improved endometrial thickness, pregnancy
and delivery rates [3]. In the same way, Acharya et al. found an
improvement in endometrial thickness and pregnancy rate of
40% in treated patients [64]. Similarly, it is reported that use of
vitamin E cause adequate ET in 52% of patients as well as growth
of the glandular epithelium, number of blood vessels and VEGF
protein expression [3]. Also, Cicek and colleagues found that
4 M. Eftekhar et al. / Middle East Fertility Society Journal 23 (2018) 1–7
Vitamin E administration could improve the endometrial thickness
but not implantation and ongoing pregnancy rate in women with
unexplained infertility [65]. Pentoxifylline has been used clinically
in the treatment of vascular abnormalities, and is also a good
choice for radiation-induced fibrosis. However the precise mecha-
nism has not yet been known, the influence is improved while it
use in combination with vitamin E [66]. One study assessed the
antifibrotic effect of PTX by a combination of PTX and tocopherol
(vitamin E) in patients with a thin endometrium who were joined
an oocyte donation program. Eighteen oocyte recipients who failed
to improve endometrial thickness after receiving vaginal micro-
nized estradiol were included the study. The patients received a
combination of PTX (800 mg/day) and vitamin E (1000 IU/day)
for 6 months. Pregnancy rate, endometrial thickness and ovarian
function have been developed [3].
3.8. Nitroglycerin
Nitric oxide (NO) is a vasodilator that involved in endometrium
reception and regulation of reproductive cycle. NO administration
may have beneficial effects on in women with a thin endometrium.
However there is no publication on this issue, two studies reported
that usage of glyceryl trinitrate patch induces a reversible rise in
subendometrial blood flow velocity during days 9–12 of the men-
strual cycle [67] with no positive effect on implantation or preg-
nancy rates among patients with implantation failure [68].
3.9. Granulocyte colony stimulating factor (G-CSF)
It is stated that G-CSF may increase the endometrial thickness
and the chance of pregnancy in the patient with extremely thin
endometrium [69]. In the same way, Tehraninejad and coworkers
showed that infusion of G-CSF in endometrial cavity is safe and
possibly effective to increase endometrial growth in patient with
thin and unresponsive endometrium [70]. Endometrial perfusion
with G-CSF is effective in expanding unresponsive thin endome-
trium to at least minimal thickness of 7 mm, which was resistant
to estrogen and vasodilators. A growth occurred in endometrial
thickness can be detected within 48–72 h of G-CSF administration
[71]. This approach in infertile women on the day of hCG adminis-
tration and in combination with second fusion resulted in low but
very reasonable clinical pregnancy rate [72]. In contrast, a random-
ized clinical trial in normal IVF patients, G-CSF did not increase
endometrial thickness, implantation rates, or clinical pregnancy
rates [73]. Some other studies confirmed these results. Eftekhar
et al. failed to demonstrate that G-CSF improve endometrial thick-
ness but they reported G-CSF positive effect on chemical and clin-
ical pregnancy rate of the infertile women with thin endometrium
in frozen-thawed embryo transfer cycle [74]. Otherwise, Li and col-
leagues stated effectiveness of G-CSF in developing embryo
implantation and clinical pregnancy rate among infertile women
with thin endometrium [75].
3.10. Platelet-rich plasma (PRP)
PRP is blood plasma prepared from fresh whole blood that has
been supplemented with platelets. It is collected from peripheral
veins and contains several growth factors and cytokines [76]. As
soon as platelets are motivated in PRP, cytokines and growth fac-
tors turn out to be active and are secreted within 10 min. Recently,
PRP has been commonly applied in different clinical situations;
however, little is identified about the application of PRP in the
treatment of thin endometrium. For the first time, Chang and
coworkers introduced intrauterine infusion of PRP as a new
approach for the treatment of thin endometrium. They evaluated
the efficacy of PRP in the therapy of infertile women with thin
endometrium. Five women with thin endometrium after standard
hormone replacement therapy (HRT) who were candidate for IVF
included the study. PRP was prepared from autologous blood by
centrifugation, and infusion of 0.5–1 ml of PRP into the uterine cav-
ity on the 10th day of HRT cycle was performed. If endometrial
thickness failed to improve 72 h later, PRP infusion was done 1–2
times in each cycle. Embryos were transferred while the endome-
trium thickness reached more than 7 mm. Endometrial growth as
well as successful pregnancy was occurred in all the patients after
PRP infusion [77]. In the same way, ten patients with the history of
inadequate endometrial growth in FET cycles were enrolled in
another study. Intrauterine infusion of PRP was performed for all
patients. According to the results endometrial thickness increased
and 50% of patients achieved pregnancy [78].
3.11. Neuromuscular electrical stimulation (NMES)
NMES defined as electrical stimulation of a group of muscles
through electrodes located on the skin. It is demonstrated that
NMES in an effective method for treatment of pelvic pain, low back
pain, stress urinary incontinence, sexual dysfunction, and constipa-
tion [79]. A total of 40 patients with thin endometrium undergoing
FET cycle divided to NMES-treated and control group. Endometrial
thickness was improved in 60% of patients after the NMES therapy
and the difference was statistically significant. Moreover, NMES
therapy resulted in higher pregnancy [80].
3.12. Stem cell therapy
It is indicated that endometrial stem cells are present in both
basalis and functionalis layers of the human endometrium, and
these cells play a key role in regenerating endometrial lining dur-
ing each menstrual cycle [81,82]. It is also showed that human
endometrial adult stem cells are capable to produce human endo-
metrium after transplantation in NOD-SCID mice renal capsules
[83]. Other studies claimed that transplanted BMSCs into rats’ uter-
ine cavity [84] as well as transplantation by tail vein IV injection
[85] resulted in a remarkable thicker endometrial lining and higher
expression of cytokeratin, vimentin, integrin acb3, and leukaemia
inhibitor factor. Likewise it is revealed by Taylor and colleagues
that non-endometrial stem cells such as hematopoietic and non-
hematopoietic bone marrow-derived stem cells (BMDSCs) could
induce endometrial regeneration [86]. Interestingly male origin
BMDSCs were found in endometrium of female bone marrow
transplant recipients [87]. Moreover, it is demonstrated that
BMDSCs induce regeneration of endometrial cells by paracrine sig-
naling [88] and this effect is twofold higher during uterine injury
rather than monthly cyclic regeneration of the endometrium
[89]. Furthermore the influence of BMDSC on endometrial renewal
after injury was confirmed in several animal studies [90,91]. On the
other hand Hunter et al. did not found any significant improve-
ments in endometrial lining following stromal vascular fraction
cells (SVF) treatment [92].
Based on aforementioned researches, the effects of bone mar-
row stem cells in the treatment of Asherman’s syndrome and thin
endometrium were evaluated in murine model. The numbers of
conceived mice were 9 of the 10 in the BMDSC transplant group
in comparison with 3 of 10 in the non-transplanted group [93].
Similarly, Kilic and coworkers treated Asherman’s syndrome
among Wistar albino rats using either mesenchymal stem cells
(MSCs) or oral estrogen or combination of these two methods.
Fibrosis decreased but vascularization and immunehistochemical
staining increased in all treated groups compare to controls [94].
In a recent study, seven types of BMDCs in the endometrial
renewal in mice were investigated and results showed that MSCs
and EPCs together with mOct4(+) BM-HypoSCs prompted the high-
 M. Eftekhar et al. / Middle East Fertility Society Journal 23 (2018) 1–7
est degree of regeneration [95]. There are few reports regarding
human application of stem cells for the treatment of thin endome-
trium. In a plan of autologous stem cells therapy, endometrial
angiogenic stem cells were isolated from bone marrow of a patient
with Asherman’s syndrome. These cells were infused into the
endometrial cavity and the results were endometrial thickness of
8 mm and a confirmed clinical pregnancy following IVF [96]. Sim-
ilarly six cases of refractory Asherman’s syndrome with the history
of failed standard treatment received sub-endometrial autologous
stem cell implantation followed by exogenous oral estrogen ther-
apy. The endometrial thickness was significantly improved in com-
parison with pretreatment condition. Additionally five women of
six patients resumed menstruation [97].
In a most recent experimental study, 16 patients with refrac-
tory Asherman’s syndrome or endometrial atrophy received autol-
ogous CD133 + BMDSCs through the spiral arterioles by
catheterization. Endometrial thickness increased about 2.4 mm
and 1.5 mm in Asherman’s syndrome and endometrial atrophy
patients respectively. Three patients obtained spontaneous preg-
nancy as well as seven pregnancies which attained after ART [98].
3.13. Endometrial receptivity array (ERA)
Challenges to catch an appropriate marker for endometrial
receptivity led to definition of a molecular test; the endometrial
receptivity array (ERA). It is a molecular diagnostic tool based on
the transcriptomic signature of human endometrial receptivity.
The test comprises 238 genes which are differentially expressed
between varied genetic profiles. This array is able to predict per-
sonalized window of implantation irrespective of her endometrial
histology. The bioinformatics predictor categorizes an endometrial
sample as ‘‘receptive” or ‘‘non-receptive” [99]. Sensitivity and
specificity of ERA are 0.99 and 0.88 respectively [100]. Cruz and
Bellver reported a healthy term live birth in a 35-year-old cancer-
ous woman following treatment with chemotherapy and radio-
therapy. The woman suffers ovarian failure, hypoplastic uterus
and atrophic endometrium. The recognition of a receptive endome-
trium using ERA and ovum donation resulted in a successful preg-
nancy in this poor prognosis case [101]. Another study used
personalized embryo transfer on the day elected by ERA in the
Indian population. After personalized ET in patients with persis-
tently thin endometrium, the pregnancy rate of 66.7% was attained
in this group. Application of ERA revealed that the endometrium in
75% of these patients was receptive regardless of its thickness of 6
mm or less [12].
In conclusion, a receptive endometrium is an essential part of
embryo implantation process, and inadequate endometrial growth
is associated with lower possibility of pregnancy. Many treatment
modalities have been applied to improve endometrial receptivity,
but their efficacy remains controversial. Large randomized trials
should be conducted to evaluate method, dosage, timing of admin-
istration and outcomes of these treatment approaches. Stem cell
therapy is considered as a very favorable option for the most cases,
even though, more investigation is necessary to evaluate the safety
and cost-effectiveness of this technique. ERA is an accurate test for
diagnosing endometrial receptivity and could establish a personal-
ized window of implantation in cases with thin endometrium.
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