Middle East Fertility Society Journal (2017) 22, 1–12

Middle East Fertility Society

Middle East Fertility Society Journal

www.mefsjournal.org
www.sciencedirect.com

REVIEW

Modern management of thin lining

Youssef Mouhayar a, Fady I. Sharara b,c,*

a
Dept of OB/GYN, University of Miami/Jackson Memorial Hospital, Miami, FL, United States
b
Virginia Center for Reproductive Medicine, Reston, VA, United States
c
Dept of OB/GYN, George Washington University, Washington, DC, United States

Received 31 May 2016; revised 23 June 2016; accepted 4 September 2016

Available online 4 October 2016

KEYWORDS Abstract Objective: To define ‘‘thin” endometrium in fertility treatment, and to critically explore
Thin endometrium; the available treatment options.
Endometrial thickness; Design: A review of the scientific literature.
Endometrial pattern; Setting: N/A.
Pregnancy rates; Methods: An electronic literature search pertaining to patients with ‘‘thin” endometrium under-
G-CSF; going fertility treatment was performed through April 2016.
Stem cell therapy Results: Adequate endometrial growth is an integral step in endometrial receptivity and embryo
implantation. Whether idiopathic or resulting from an underlying pathology, a thin endometrium
of <7 mm is linked to a lower probability of pregnancy; however, no reported thickness excludes
the occurrence of pregnancy. Several treatment modalities have been studied and include extended
estrogen, gonadotropin therapy, low-dose hCG, tamoxifen, pentoxifylline, tocopherol, l-arginine,
low-dose aspirin, vaginal sildenafil, acupuncture and neuromuscular electric stimulation, intrauter-
ine G-CSF, and stem cell therapy. All treatment modalities except vaginal sildenafil, intrauterine
GCF, and stem cell therapy were inconsistent in showing significant improvement in pregnancy
rates. Early results of stem cell therapy trials seem promising.
Conclusions: EMT <7 mm is associated with lower probability of pregnancy in ART. Vaginal
sildenafil appears to be a reasonable first line therapy option, and G-CSF appears to be a potential
second option, while stem cell therapy seems to be a promising new treatment modality.
Ó 2016 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/).

* Corresponding author at: Virginia Center for Reproductive Medicine, 11150 Sunset Hills Rd, Suite 100, Reston, VA, United States.
E-mail address: fsharara@vcrmed.com (F.I. Sharara).
Peer review under responsibility of Middle East Fertility Society.

Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.mefs.2016.09.001
1110-5690 Ó 2016 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 Y. Mouhayar, F.I. Sharara

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1. Hormonal adjustment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2. Pentoxifylline and tocopherol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.3. Low-dose aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.4. Acupuncture, neuromuscular electric stimulation and electro-acupuncture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.5. Vaginal sildenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.6. Granulocyte colony-stimulating factor (G-CSF). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.7. Stem cell therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1. Introduction (18,22,35–58). Moreover, most of the reports used a cutoff

Embryo implantation is a very delicate and well-orchestrated
process that is governed by the interaction between several
maternal and embryonic factors, ultimately resulting in adher-
ence of the blastocyst to the endometrium (1–5). For a short
period of time during the normal menstrual cycle, the endome-
trium represents the fertile ‘‘soil” for the implanting embryo
(6). The human endometrium undergoes complex changes, in
response to circulating estrogen and progesterone, which cul-
minate at the mid-luteal phase of the menstrual cycle when it
becomes suitable to host the blastocyst (7–9). These changes
occur at the morphological, biochemical, and molecular levels;
any faux pas may result in failed implantation (10–13). Identi-
fying a receptive endometrium is essential; however, an ideal
method that can reliably predict endometrial receptivity has
yet to be determined. In clinical practice, high-resolution ultra-
sonography is routinely used to monitor follicular develop-
ment and endometrial responsiveness during controlled
ovarian stimulation. Several ultrasound markers, such as
endometrial thickness (EMT), pattern, blood flow impedance,
and uterine volume have been evaluated for their predictive
role of endometrial receptivity; however, they had low speci-
ficity and positive predictive value for detecting a receptive
endometrium (14,15). Endometrial patterns, such as a triple-
layer endometrium on day of human chorionic gonadotropin
(hCG) trigger or oocyte retrieval and embryo transfer might
be a better predictor of implantation than endometrial thick-
ness (16–25). A certain endometrial development however, is
an integral part of a receptive endometrium. Despite that a
minimal endometrial thickness of 6 mm has been reported to
be essential for achieving implantation in assisted reproductive
technologies (ART), successful pregnancies were documented
with a minimum EMT of 4 mm (26–29). In fact and up to this
date, there is no consensus on a cutoff value of an EMT below
which implantation rates even decline in ART. Using receiver
operating characteristics (ROC) area under the curve, a cutoff
limit of endometrial thickness (on day of hCG trigger) above
which implantation could be predicted was not detected by
three reports, whereas two studies reported a threshold thick-
ness of 8 mm (30–34). While several reports showed that
endometrial thickness has a predictive value for successful
pregnancies in ART, others have demonstrated the opposite
EMT of 7 mm while others used 6 mm, 8 mm, 9 mm, or
10 mm (18,32–34,38,40,44,46–52,56–60).
Several mechanisms have been proposed to explain the
underlying pathophysiology of thin endometrium. Intrauterine
adhesions, ovarian stimulation with clomiphene citrate (CC),
as well as prolonged use of progesterone, or combined oral
contraceptive pills have been associated with thin endome-
trium (61–63). Vascular epithelial growth factor (VEGF),
which plays a critical role in angiogenesis, appears to be an
important factor in the pathophysiology of thin endometrium.
Adequate endometrial development, which is hormonally
mediated, is highly dependent on adequate blood supply.
Miwa et al. elegantly described that with increased impedance
across the radial uterine arteries, there is resultant decrease in
VEGF expression and subsequent poor vascular development,
resulting in thin endometrium (64).
In 2008, Senturk et al. reviewed thin endometrium in ART
and the available treatment modalities (extended estrogen
administration, vaginal sildenafil, vitamin E, pentoxifylline,
and luteal phase GnRH-a supplementation), and concluded
that these were ineffective (65). More recently, Lebovitz
et al. concluded that the treatment of ‘‘thin” endometrium
remains a challenge, with only minor improvements achieved
with the currently available treatment modalities (66). A recent
systematic review and meta-analysis of 10,724 cases showed
that EMT as an independent variable is not predictive for
the occurrence of pregnancy (67). This meta-analysis however,
found that the most commonly reported cutoff of 7 mm
occurred in only 2.4% of the cases (260/10,724), and this cutoff
was associated with a significant drop in the probability of
pregnancy (67). We have elected to review this topic as new
treatment modalities emerge. Here we provide a more thor-
ough review of the available literature to date, aiming to define
‘‘thin” endometrium in infertile patients, and to critically ana-
lyze the proposed treatment modalities.
2. Materials and methods
We performed a review of the literature on thin endometrium,
its pathophysiology, and treatment. Abstracts, case reports,
original, and review articles were considered. A computer-
based systematic literature review was performed through
Modern management of thin lining
April 2016. The Cochrane database, PubMed, Medline reg-
istries, and other online sources were searched using the broad
terms: thin endometrium, thin endometrium and IVF, thin
endometrium and ART, and treatment of thin endometrium.
The titles and abstracts were screened for relevance, and rele-
vant articles were analyzed in detail to determine which studies
could be included in the review. Furthermore, the references
cited in relevant studies and review articles were hand searched
to identify further relevant studies. Studies were considered eli-
gible if they were conducted to assess or compare different
treatment modalities of thin endometrium. Changes in mean
endometrial thickness and pregnancy rates were the two prin-
ciple summary measures, and were independently extracted
from individual studies.
3. Results
3.1. Hormonal adjustment
Endometrial proliferation is dependent on serum estrogen
levels, which results in progressive growth of the functional
endometrium in the proliferative phase. On this basis, patients
with thin endometrium were offered supplemental exogenous
estrogen. Studies were mostly in frozen-thawed embryo trans-
fer (FET) cycles and in vitro maturation (IVM). In 2006, Chen
et al. randomized 36 patients with endometrial thickness
<8 mm to either extend estrogen treatment followed by
FET, or to proceed directly with embryo transfer (68). The
study group received oral estradiol valerate for 14–82 days, fol-
lowed by embryo transfer when the EMT was greater than
8 mm. The endometrial thickness was significantly higher after
treatment in patients who received the estradiol treatment (8.6
± 0.7 mm vs. 6.7 ± 0.9 mm, P = 0.031), with a significantly
higher pregnancy rate than in patients who proceeded with
embryo transfer (38.5% vs. 4.3%, P = 0.016). In this study
however, the EMT was similar in patients who conceived com-
pared to those who did not, in both the study and control
groups (68). Shen et al. presented a case of a 37 year-old
woman with a refractory thin endometrium (<6 mm) who
was treated with extended estrogen supplementation for 9 days
followed by controlled ovarian hyperstimulation, and this
combination resulted in a live twin birth at 36 weeks (69).
Poor endometrial development has also been suggested to
be a reason behind the lower pregnancy rates in IVM cycles.
To improve endometrial development in IVM cycles, Elizur
et al. compared the administration of low-dose human meno-
pausal gonadotropin (hMG) and micronized 17b-estradiol
supplementation in IVM cycles with thin endometrium (70).
The authors noted a significant improvement in endometrial
thickness from <6 mm to 7.7 ± 1.8 mm and 7.3 ± 1.7 mm
with low-dose hMG and 17b-estradiol, respectively, without
a significant difference between the two groups. There was
no difference in pregnancy rates between the two arms of the
study, nor was there an untreated control group for compar-
ison (70).
Luteal phase support with gonadotropin-releasing hormone
agonists (GnRH-a) is another form of hormonal manipulation
that was employed in patients with thin endometrium undergo-
ing IVF. Qublan et al. prospectively randomized 120 patients
undergoing IVF with thin endometrium (67 mm), to either
GnRH-a or placebo during luteal support (71). Sixty patients
3
received 0.1 mg of Triptorelin on days of egg retrieval, embryo
transfer, and 3 days after embryo transfer, while the remaining
60 patients served as the control group. EMT increased from
6.89 ± 0.24 mm to 8.92 ± 1.6 mm in the study group which
was significantly higher than the increase noted in the control
group which was from 6.83 ± 0.26 to 7.12 ± 0.45 mm (8.92
± 1.6 mm vs. 7.12 ± 0.45 mm, P < 0.05). Pregnancy rate
was also significantly higher in the study group vs. the control
group (36.6% vs. 13.7%, P < 0.01) (71).
Adding low-dose human chorionic gonadotropin (hCG)
during endometrial preparation with estradiol was investigated
as well. In a pilot study by Papanikolaou et al. seventeen
patients with resistant thin endometrium (<7 mm) during
fresh or frozen donor-embryo cycles were recruited (72). 150
IUs of hCG were administered daily for seven days starting
on days 8 or 9 of estrogen administration. The mean EMT
increased from an average of 5.18 mm to 6.01 mm
(P = 0.008); however, 5 of 17 patients (29.4%) did not experi-
ence any improvement in EMT. The pregnancy rate following
treatment was 52.9% (9/17 patients), including pregnancies in
two patients who had not improved their EMT after treatment
(72).
Clomiphene citrate (CC) has been widely utilized for ovula-
tion induction. Similar to other selective estrogen receptor
modulators (SERMs), CC has mixed estrogenic and anti-
estrogenic effects along the hypothalamic-pituitary-gonadal-u
terine axis (73). In fact, CC’s positive effects in treating infer-
tility by inducing ovulation are counteracted by its negative
effects on endometrial proliferation (74–76). Tamoxifen
(TMX) on the other hand is another SERM that is similar
to CC but has an estrogen agonist effect at the level of the
endometrium, and on this basis it was suggested that TMX
could be used for ovulation induction (77). In a prospective
trial, Wang et al. had 131 patients with various infertility diag-
noses who had failed to develop an EMT of 8 mm (78).
Patients were allocated to either TMX or CC with alternating
gonadotropins. Sixty-one patients (81 cycles) received 40 mg of
tamoxifen daily on days 3–9 and 70 patients (82 cycles)
received 100 mg CC daily on days 3–7 with alternating hMG
(150 IUs). The TMX group had a significantly thicker EMT
on day of hCG trigger vs. CC with alternating hMG (10.8
± 2.3 mm vs. 6.7 ± 1.3 mm, P < 0.001), as well as a higher
clinical pregnancy rate following intrauterine insemination
(32.1% vs. 15.9%, P = 0.015) (78). In 2010, Reynolds and col-
leagues retrospectively reviewed 19 women who had failed to
develop an EMT of P7 mm during OI with CC and who were
switched to OI with TMX (79). The mean EMT, measured on
either day 12 or 14 of the cycle, increased from 5.5 ± 0.8 mm
to 8.8 ± 1.3 mm, P < 0.001 in the TMX treated cycles with a
pregnancy rate of 42.1% (79). A recent prospective random-
ized trial by Morad et al. compared OI with TMX versus
CC plus vaginal sildenafil in 65 patients with EMT < 7 mm
in a previous OI cycle with CC only (80). Of those, 34 were
randomized to receive TMX 40 mg daily on days 3–7 of the
cycle, and 31 patients to receive 100 mg of CC daily with
25 mg of vaginal sildenafil four times per day on days 3–7 of
the cycle. EMT, measured on day of hCG trigger, significantly
increased in both groups in comparison with the previous CC
only cycles: from 5.7 ± 1.2 to 8.81 ± 1.32, P < 0.05 in TMX
group and from 5.5 ± 1.4 mm to 9.3 ± 1.2 mm; however,
there was no difference in pregnancy rates between the two
groups after IUI (18.75% vs. 27.59%, P > 0.05) (80). Most
4 Y. Mouhayar, F.I. Sharara
recently Chen et al. reported three cases of recurrent unrespon-
sive thin endometrium (<6 mm) who were successfully treated
with TMX to increase their EMT (81). Patients were undergo-
ing programmed FET, and TMX was used to simulate
endometrial proliferation. Patients were given 20 mg of TMX
daily for 5 days. The endometrial thickness increased to 7.7,
7.8, and 8.1 mm in the first, second, and third patient respec-
tively, 7–11 days after TMX withdrawal with three clinical
pregnancies and two healthy deliveries (81).
3.2. Pentoxifylline and tocopherol
Pentoxifylline (PTX) is a methylxanthine derivative used to
treat vascular diseases. In vivo, it has been reported to increase
erythrocyte flexibility, to vasodilate, and to inhibit inflamma-
tory reactions and tumor necrosis factor (TNF) (82). PTX
and tocopherol (Vitamin E) combination has been reported
to improve endometrial thickness in patients with radiation-
induced thin endometrium, and was therefore tried in oocyte
recipients with thin endometrium unresponsive to estradiol
therapy. In 2002, Lédée-Bataille et al. administered PTX and
tocopherol (400 mg and 500 IU respectively twice daily) to
18 oocyte-donor recipient patients with thin endometria
(66 mm) who had failed to respond to micronized vaginal
estradiol (83). After six months of treatment, the EMT signif-
icantly increased by 1.3 mm ± 1 mm. The pregnancy and
delivery rates were 33% and 27%, respectively. However, there
was no significant difference in the endometrial thickness
between those who conceived and those who did not, before
or after the treatment (83). The mechanism of action of this
combined treatment on endometrial thickness and pregnancy
outcome is unclear; however, it is hypothesized that it inhibits
inflammatory reactions and decreases TNF-alpha levels. In a
case series by Letur-Konirsch and Delanian, three oocyte-
donor recipients with estrogen-resistant thin endometria (mean
EMT 4.9 mm) were treated with combined PTX and toco-
pherol (800 mg and 1000 IU respectively) for 9 months (84).
There was an increase in the endometrial thickness to a mean
of 7.4 mm, and 2 of 3 patients conceived (84). Acharya et al.
also administered combined PTX and tocopherol (800 mg
and 1000 IU respectively) to 20 infertile patients with thin
endometrium over an average duration of 8.1 months (85).
There was a significant increase in EMT at the end of the treat-
ment (4.9 ± 1.5 mm vs. 7.4 ± 0.9 mm, P = 0.001) resulting in
a 40% pregnancy rate (85).
The effects of administering vitamin E alone were also stud-
ied. In a prospective observational trial, 600 IU of Vitamin E
daily significantly increased the endometrial thickness in
52% of patients with an EMT < 8 mm (7.2 mm vs. 8.3 mm,
P < 0.05) (86). In that same trial, L-Arginine (6 grams/day)
treatment was also successful in six out of 9 (67%) patients
(7.4 mm vs. 8.0 mm, P < 0.05). In a prospective randomized
controlled trial by Cicek et al. 400 IU of vitamin E was admin-
istered to patients with unexplained infertility during con-
trolled ovarian hyperstimulation (COH) (87). There was a
significant increase in EMT to 9.6 ± 2.1 mm vs. 8.2
± 2.0 mm in patients who received vitamin E with clomiphene
citrate for ovulation induction compared to those who did not
(P = 0.001). However, there were no significant differences in
implantation rates and ongoing pregnancy rates between the
two groups (87).
3.3. Low-dose aspirin
Low-dose aspirin is hypothesized to increase endometrial
blood flow by decreasing impedance across the uterine artery.
It has been previously reported that low-dose aspirin results in
lower pulsatility index of the uterine artery and subsequently
improves pregnancy rates (88). In their report on low-dose
aspirin use in frozen-thawed embryo transfers Check and col-
leagues noted an increase in mid-luteal phase EMT when com-
pared to controls (89). Weckstein et al. randomized 28 patients
with thin endometrium (<8 mm) in an oocyte donation pro-
gram to either low-dose aspirin (81 mg) with estrogen or estro-
gen only (90). There was no significant difference between the
aspirin group and non-aspirin group (1.6 ± 1.5 mm vs. 0.9
± 0.8, respectively). Despite the increased implantation rate
in the aspirin group, there was only a trend for improved clin-
ical pregnancy rate in the aspirin treatment group (60% vs.
31%). Interestingly, in those patients whose endometrial thick-
ness remained less than 8 mm in the two groups, the clinical
pregnancy rate was significantly higher for those who received
aspirin (83% vs. 25%, P < 0.05) (90). In another prospective
randomized trial, patients with thin endometrium (<8 mm)
undergoing COH and intrauterine insemination (IUI) were
randomized to either receive 100 mg of aspirin daily starting
day 1 of the cycle until the pregnancy test, or no aspirin ther-
apy (91). There were no significant differences in the mean
EMT after treatment between the aspirin group and the non-
aspirin group (7.2 ± 1.8 vs. 5.8 ± 1.4, respectively). The clin-
ical pregnancy rate however, was significantly higher in the
aspirin group vs. non-aspirin group (18.4% vs. 9.0%,
P = 0.036) (91).
3.4. Acupuncture, neuromuscular electric stimulation and
electro-acupuncture
Acupuncture, one of the oldest interventions of traditional
Chinese medicine, has been utilized in several obstetrical and
gynecologic conditions, including infertility. Several reports
were able to show that acupuncture may improve pregnancy
rates in ART (92,93). Two other reports were able to show that
electro-acupuncture was able to reduce blood flow impedance
across the uterine artery in infertile patients undergoing IVF
(94,95). In a prospective, non-randomized trial, Stener-
Victorin was able to demonstrate that electro-acupuncture
reduced uterine artery blood flow impedance in 10 infertile
but otherwise healthy patients with baseline impedance (94).
In a randomized controlled trial (RCT), Ho et al. treated thirty
infertile patients with electro-acupuncture twice weekly for
4 weeks, whereas 14 other patients served as a control group
(95). There was a significant reduction in the uterine artery
blood flow impedance in the study compared to the control
group, without a significant difference in pregnancy rates
between the two groups (95). In another recent single-
blinded randomized controlled trial, Shuai et al. treated
patients undergoing FET, with either transcutaneous electrical
acupuncture point stimulation (TEAS) or mock TEAS. EMT
on day of hCG trigger was similar between the two groups
(11.26 ± 1.5 mm vs. 10.74 ± 1.54 mm), whereas the study
group had a higher number of triple-line endometrium
(91.2% vs. 41.2%, P = 0.002), and a higher clinical pregnancy
rate (44.1% vs. 20.6%, P = 0.038) (96). However, as far as we
Modern management of thin lining
know, there have not been any studies on improving endome-
trial thickness using acupuncture.
Pelvic floor neuromuscular electrical stimulation (NMES)
has been used in patients with thin lining. In their preliminary
report, Bodombossou-Djobo et al. evaluated 41 subjects with
an EMT 6 7 mm who failed to conceive in two prior ART
cycles (97). Twenty had NMES in their subsequent FET cycle,
whereas 21 proceeded directly with FET. NMES was applied
daily for a total of 3–4 days starting on day 9 of the stimula-
tion. EMT significantly increased in the treatment group com-
pared to the control group (7.93 ± 1.42 mm vs. 6.78
± 0.47 mm, P = 0.002) but without a significant difference
in the clinical pregnancy rates between the two groups (97).
3.5. Vaginal sildenafil
Sildenafil citrate is phosphodiesterase-5 inhibitor that
enhances the vasodilatory effects of nitric oxide, which in turn
increases subendometrial blood flow. In 2000, Sher et al.
reported four patients who had previously had an EMT
between 5–7 mm in a prior failed IVF or IUI cycles, and
who were all given vaginal sildenafil 25 mg four times per
day for 8–12 days during COH (98). The EMT measured on
day of hCG administration and was found to be between 8
and 12 mm (98). The same four patients had also undergone
a prior mock cycle with leuprolide acetate and received the
same daily dose of vaginal sildenafil for 7 days, then 7 days
of placebo followed by vaginal sildenafil and estradiol for
another 7 days. The pulsatility index decreased after treatment
with sildenafil, but was back to baseline after 7 days of pla-
cebo, indicating increased diastolic blood flow after sildenafil
administration (98). Two years later the same group adminis-
tered vaginal sildenafil (25 mg, 4 times daily) on days 3
through 10 in 105 patients undergoing IVF who had failed
to develop an EMT of 9 mm in prior failed IVF cycles (99).
The patients had various causes leading to poor endometrial
development, including pregnancy-related endometritis, DES
anomalies, fibroids, adenomyosis, and idiopathic. Seventy-
three patients (70%) experienced an increase in their EMT to
greater than 9 mm, and had a significantly higher implantation
and ongoing pregnancy rates when compared to those who
failed to respond (29% vs. 2%, P < 0.01, and 45% vs. 0%,
P < 0.01 respectively). The overall ongoing pregnancy rate
in that cohort was 31.4% (33/105) (99). In a smaller trial by
Check et al. 16 patients who had failed to attain an EMT of
8 mm during FET cycles were assigned to either vaginal silde-
nafil or vaginal estradiol in addition to oral estradiol (100).
Nine patients received 25 mg of vaginal sildenafil four times
daily from days 3 to 9 with no significant change in their
EMT after treatment (6.3–6.4 mm). Of the remaining seven
patients who received vaginal estradiol, 6 were previously
given vaginal sildenafil without improvement in EMT. The
pregnancy rate was only 16.6% (1 out of 6 attempted FET)
(100).
Asherman’s syndrome (AS) is another cause of suboptimal
endometrial development that can lead to subfertility. Zinger
et al. successfully treated two cases with subfertility and thin
endometrium (<7 mm) during previous stimulated cycles (oral
estradiol or clomiphene citrate) (101). Vaginal sildenafil was
administered for 8–15 days during the treatment cycles. One
patient experienced an increase in EMT from 6.5 mm to
5
8.9 mm, and the second patient from 5.0 mm to 6.6 mm. Both
patients had a full term healthy singleton deliveries (101). In
another trial by Takasaki et al. vaginal sildenafil significantly
increased the EMT in 11 out of 12 patients (92%) from
7.1 mm to 9.4 mm (P < 0.01), with a 50% pregnancy rate after
12 IVF cycles (102). Similar positive effects on improving
EMT were also noted by Morad and colleagues where 31
patients experienced significant improvement in EMT from
5.5 ± 1.4 mm to 9.3 ± 1.2 mm (80). Most recently, Eid et al.
administered vaginal sildenafil to 22 patients with an EMT
of 7 mm and elevated pulsatility index (PI > 0.3) for a total
of 7 days between ovulation trigger and embryo transfer
(103). Sixty-eight percent (15/22) of patients experienced
improvement in EMT and a decrease in their PI. Implantation
rates and pregnancy rates were higher in patients who
responded to treatment (26% vs. 7%, and 40% vs. 14%,
respectively) (103).
3.6. Granulocyte colony-stimulating factor (G-CSF)
G-CSF, initially described as a hematopoietic growth factor,
has been shown to have important functions in nonhematopoi-
etic cells, including the endometrium, and has a potential role
in promoting early endometriotic lesions in a murine model
(104). Gleicher et al. hypothesized that G-CSF might have a
direct role promoting endometrial growth, and reported a case
series of 4 patients with thin endometria between 3 and 6.5 mm
who failed to improve with oral and vaginal estrogen as well as
with vaginal sildenafil (in one of the patients) (105). All four
patients had intrauterine G-CSF infusion (300 lg) 2–9 days
before ET, and had a significant increase to at least 7 mm
within 48 h. All four patients conceived, one of which had an
ectopic (105). Two years later, the same group performed a
prospective pilot cohort study of 21 patients undergoing IVF
who had EMT < 7 mm on the day of hCG trigger despite oral
and vaginal estrogen as well as vaginal sildenafil (106). All
patients received 300 lg of G-CSF intrauterine infusion 6–
12 h prior to hCG trigger. A second infusion was needed in
only 3 of 21 patients (14.3%). Overall, EMT increased from
an average of 6.4 ± 1.4 mm to 9.3 ± 2.1 mm (P < 0.001)
after G-CSF treatment, but did not differ between those who
conceived and those who did not. The overall clinical preg-
nancy rate in the cohort was 19.1% (106).
Lucena et al. reported a patient with thin endometrium
(<5.7 mm) during an in vitro maturation (IVM) cycle who
was given 300 lg of intrauterine G-CSF on day of oocyte
retrieval (107). The EMT subsequently improved to 8.9 mm,
and embryo transfer resulted in a full term delivery (107).
Check and colleagues reported a patient who had multiple
IVF-ET and FET cycle failures due to ‘‘thin” endometrium
of 6 mm despite treatment with oral and vaginal estrogen as
well as vaginal sildenafil (108). The patient was given intrauter-
ine G-CSF as described by Gleicher et al. (105); however, her
EMT was only 5 mm and had a negative pregnancy test after
embryo transfer (108). Li et al. then reported on 69 patients
who failed to develop an EMT greater than 7 mm in FET
cycles despite escalating endometrial preparation protocols
(109). Fifty-nine patients were included in this retrospective
analysis, of which 34 opted for G-CSF treatment (28 refused),
and received intrauterine G-CSF (100 lg) on the day of ovula-
tion, or day of progesterone start, or day of hCG administra-
6 Y. Mouhayar, F.I. Sharara
tion (109). The cycle cancelation rate due to thin endometrium
was lowest in the G-CSF treatment group (69.39% vs. 48.75%
vs. 17.5%, P < 0.05 self-controlled vs. control vs. treatment
groups, respectively), and there was a trend toward better
implantation (15.8% vs. 7.89%), and clinical pregnancy rates
(30.30% vs. 20.0%) in the G-CSF group compared to both
control groups (109). Kunicki et al. administered intrauterine
G-CSF (100 lg) to 37 patients who failed to develop an
EMT of 7 mm on day of hCG trigger during prior IVF cycles.
In this prospective study, intrauterine G-CSF was given 6–12 h
prior to hCG trigger (based on Gleicher’s earlier report), which
resulted in a significant increase in EMT from 6.74
± 1.75 mm, to 8.42 ± 1.73 (P < 0.001) within 72 h (110).
The clinical pregnancy rate was 18.9%; however, there was
no difference in the EMT between patients who conceived
and those who did not (110).
Recently, Barad et al. tried to expand the use of G-CSF on
endometrial thickness for all patients undergoing IVF or FET,
regardless of endometrial thickness. The study group received
300 lg/cc G-CSF (on the day of HCG trigger), while the con-
trol group received placebo (saline) (111). The EMT increased
significantly in the entire cohort by approximately 1.36 mm
without a difference between the G-CSF and control groups,
with similar clinical pregnancy rates (111).
In the most recent trial to date, Xu et al. prospectively ran-
domized 30 patients with EMT < 7 mm during frozen-thawed
embryo transfer cycles to either intrauterine G-CSF or G-CSF
with endometrial scratch, with 52 patients serving as the con-
trol group (112). G-CSF was administered ‘‘on the day that
one follicle became dominant (12 mm)”. The EMT increased
significantly after treatment (D 3.9 ± 2.0 mm, P < 0.001)
without a difference between the two subgroups (G-CSF vs.
G-CSF + scratch), and the implantation and clinical preg-
nancy rates were significantly higher in both treatment sub-
groups compared to the control group (31.5% vs. 13.9%,
P < 0.01, and 48.1% vs. 25.0%, P = 0.038 respectively) (112).
3.7. Stem cell therapy
Multiple evidence, some dating back to the early 1980s, sup-
ports the presence of endometrial stem/progenitor cells in the
basalis and functionalis layers of the human endometrium
(113–116). With the tremendous regenerative capacity of the
endometrial lining during each estrous cycle, it was hypothe-
sized that these stem/progenitor cells play an important role
in endometrial regeneration. Despite their discovery over
30 years ago, the regenerative capacity of endometrial stem
cells was just recently proven when Cervello and colleagues
demonstrated that human endometrial adult stem cells are able
to generate human endometrium after transplantation in
NOD-SCID mice renal capsules (117). The role of stem cells
in endometrial regeneration is not limited to local endometrial
progenitor cells; in fact, hematopoietic and non-hematopoietic
bone marrow-derived stem cells (BMDSCs) are recruited to
the endometrium in response to injury. Taylor showed that
BMDSCs play a role in the regeneration of endometrial stro-
mal and epithelial layers of bone marrow transplant patients
(118). These findings were further affirmed by other investiga-
tors, who showed that CD 45 + hematopoietic progenitor
cells are able to colonize the uterine epithelium and play an
important role in uterine epithelial regeneration; even more
interestingly, male origin BMDSCs were capable of composing
the endometria of female bone marrow transplant recipients,
further indicating their role in endometrial injury repair
(119,120). In their elegant study Cervello et al. recently demon-
strated that BMDSCs do not associate with endometrial side
cell population, but rather they exert their regenerative poten-
tial in a paracrine fashion, ultimately stimulating endometrial
side cell population (121). The role of BMDSC in endometrial
regeneration was further demonstrated in several murine mod-
els (122–124). In fact, uterine ischemia/reperfusion injury
results in a 2-fold increase in bone marrow-derived stem cell
recruitment to the endometrium (125). This recruitment seems
to be independent of G-CSF and only serves in uterine repair
after injury rather than monthly cyclic regeneration of the
endometrium (125).
The popularity of the regenerative potential of bone mar-
row stem cells led researchers to investigate their effects in
the treatment of Asherman’s syndrome and thin endometrium.
Alwadhi and colleagues administered BMDSCs to female mice
(via tail veins) with AS which were later bred after 3 estrous
cycles (126). 9 of 10 treated mice conceived whereas only 3
of 10 non-treated mice conceived in the non-transplanted mice
vs. 10 of 10 in the control group (126). In a similar study, Kilic
et al. induced AS in Wistar albino rats and later treated them
with either mesenchymal stem cells (MSCs) or oral estrogen or
combined MSC and oral estrogen (127). All treatment groups
demonstrated a decrease in fibrosis when compared to control,
mostly noted with combined MSC and estrogen treatment
(127).
To further elucidate the role of BMDSCs in regenerating
thin endometrium, Zhao et al. compared thin endometria
infused with bone marrow mesenchymal stem cells (BMSCs)
to controls and normal rats (128,129). The treatment groups
showed significant increase in EMT compared to the control
groups in both trials respectively (325.35 ± 75.51 lm vs.
187.53 ± 34.38 lm, P < 0.05 and 359.13 ± 49.70 lm vs.
187.53 ± 34.38 lm, P < 0.05) (128,129).
A recent comparative study analyzed the role of different
BM-derived cell subtypes in endometrial regeneration (130).
Various subtypes of BM-derived cell were injected into tail
veins of a total body irradiated murine model. Freshly isolated
unfractionated BM cells, hematopoietic progenitor cells,
endothelial progenitor cells (EPCs), mesenchymal stem cells,
and in vitro cultured mouse Oct4+ BM-derived hypoplast-
like stem cells supported endometrial regeneration (130).
The first human application was in 2011, in a case of thin
endometrium (3.6 mm) secondary to AS refractory to estradiol
treatment (131). Autologous endometrial angiogenic stem cells
were infused into the uterine cavity and was followed by high
dose estradiol valerate, aspirin (75 mg PO daily), and four
cycles of cyclical estrogen and progesterone therapy to finally
reach an EMT of 7.1 mm. Three donor oocyte embryos were
transferred resulting in a single viable intrauterine pregnancy
at 8 weeks as detected by ultrasonography (131). This was fol-
lowed by a case series of 6 patients with refractory AS who
were treated with autologous mononuclear stem cells implan-
tation. The mean EMT significantly increased from a pretreat-
ment measurement of 1.38 ± 0.39 mm to 4.05 ± 1.4, 5.46
± 1.36, and 5.48 ± 1.14 mm at 3, 6, and 9 months respectively
(P < 0.05) (132). Cervello et al. investigated whether human
CD 133 + BMDSCs would promote endometrial growth in
a murine model of Asherman’s syndrome (133). The authors
Modern management of thin lining
found that the BMDSCs engrafted around small endometrial
vessels in all damage horns and resulted in a significant
increase in epithelial gland cells proliferation via paracrine
fashion by up-regulation of thrombospondin 1 and down-
regulation of insulin-like growth factor 1 (133).
In a recent human pilot trial, Santamaria and colleagues
infused autologous CD 133 + bone marrow-derived stem cells
(BMDSCs) into the spiral arterioles of 11 patients with refrac-
tory Asherman’s syndrome and 5 patients with refractory
endometrial atrophy (134). An increase in endometrial thick-
ness lasting up to six months was noted in patients with AS
(4.3–6.7 mm) and those with refractory atrophic endometrium
(4.2–5.7 mm), with subsequent conception attempts resulting
in three spontaneous pregnancies (2, 4, and 19 months after
treatment) and seven positive pregnancies after 14 embryo
transfers (134).
4. Discussion
‘‘Thin endometrium” occurs not uncommonly in clinical prac-
tice and poses a frustrating challenge to both patients and
physicians. It is not exactly clear how thin endometrium results
in lower chances of pregnancy; however, hypotheses such the
harmful role of reactive oxygen species (ROS) or possibly
not enough ‘‘soil” to sustain the ‘‘seed” have been suggested.
The functional layer of the endometrium undergoes several
changes during the menstrual cycle relative to the basal layer,
which homes the larger-caliber oxygen-rich spiral arteries. It is
hypothesized that, with thin endometrium, the proximity to
the ROS-rich basal layer is detrimental for embryo develop-
ment and implantation (66). Clinicians are faced with the chal-
lenge of where to draw the cutoff, and how and whether to
treat it. The most widely accepted measurement is 7 mm; how-
ever, this cutoff is not absolute, as pregnancies have been
reported at much lower values (27–29). More importantly,
endometrial thickness alone does not seem to have a strong
predictive capacity for the occurrence of pregnancies in IVF
cycles, but more so a factor for the assessment of conception
probability which significantly drops below a thickness of
7 mm (63). Other key factors such as endometrial pattern play
a vital role in successful implantation as well, and may be more
important than thickness. In fact, in the setting of CCS-tested
euploid embryos, different endometrial patterns appear to
have a better correlation with the likelihood of pregnancy than
thin endometrium (25). Specifically, a mid to late secretory
stage endometrial type (type 3 endometrium) at time of ovula-
tion trigger, had a negative correlation with implantation rates
(25). Furthermore, a trilaminar endometrial pattern on
embryo transfer day might be a better prognostic factor of
cycle outcomes than endometrial thickness in IVF/ICSI cycles
(24). New diagnostic tools are emerging to aid in objectively
assessing endometrial receptivity. According to the initial find-
ings by Mahajan, the endometrial receptivity array (ERA) is
an accurate test in determining the window of implantation.
In fact 75% of patients (n = 13) with an EMT 6 6 mm in that
study were found to have a receptive endometrium according
to the customized endometrial receptivity microarray test
(135). ERA however is an invasive and costly test with early
results that must be validated with larger studies.
Over the years, multiple treatment modalities have been
studied in hopes of improving refractory thin endometrium
7
with or without Asherman’s syndrome. Extended estrogen
was beneficial in improving EMT and implantation rates in
some, but not all, patients with thin endometrium due to speci-
fic etiologies such as endometritis and multiple curettages. This
was particularly helpful for patients undergoing IVM with thin
endometrium, where extended vaginal estrogen and low dose
hMG were beneficial in improving endometrial thickness or
pregnancy rates. However, these studies were limited by small
sample size and the fact that EMT was similar between
patients who conceived and those who did not; thus, it is dif-
ficult to draw a positive conclusion regarding the benefits of
the prolonged estrogen treatment in the absence of further sup-
porting results. Two lone studies, one using luteal GnRH-a
support and another using low-dose HCG in programmed
FET cycles seem promising; however, data are lacking to draw
solid recommendations (71,72). Tamoxifen citrate, as an ovu-
lation induction agent, seems to be a good alternative to clomi-
phene citrate in patients who have poor endometrial
development during COH with IUI or FET (78–81). Treat-
ment with Tamoxifen however may be accompanied with
undesired side effects such as hot flashes, and the possibility
of increased risk of endometrial cancer and adenomyosis
(78). Long courses of PTX and tocopherol or tocopherol-
only were used in oocyte-donor recipient patients, unexplained
infertility, and patients who received radiotherapy. Although
some trials noted a significant improvement in EMT, there
was no evidence of a significant improvement in pregnancy
rates, therefore not justifying the lengthy treatment protocol.
Aspirin supplementation on the other hand had no beneficial
role in oocyte-donor recipient patients, but it showed improve-
ment in pregnancy rates without improvement in EMT in
patients with thin endometrium undergoing IUI. This
improvement in pregnancy rates however, did not reach nor-
mal expected levels for COH and IUI. Electro-acupuncture
significantly decreased blood flow impedance across the uter-
ine arteries but had no effects on pregnancy rates in IVF
cycles, and none of the conducted trials specifically addressed
patients with thin lining (94–96). While pelvic floor NMES
with biofeedback significantly improved EMT, it showed no
benefit in improving pregnancy rates (97).
Vaginal sildenafil administration was beneficial for a signif-
icant percentage of patients with various infertility diagnoses
who had two prior failed IVF cycles or of those who are under-
going ICSI. The implantation and pregnancy rates were signif-
icantly better in those patients who responded, indicating that
vaginal sildenafil could be a reasonable first line treatment
option. However these findings could be limited by the retro-
spective nature of the largest study supporting them.
Treatment with intrauterine G-CSF also received its share
of interest despite its significant cost, but the majority of trials
showed beneficial effects for G-CSF in patients with thin endo-
metrium. In fact, out of the seven reviewed papers, a case
report and one retrospective analysis in FET cycles did not
demonstrate a positive effect of G-CSF on improving EMT
in patients with thin lining (105–110,112). On the other hand,
there is no evidence to support G-CSF administration to all
patients undergoing IVF or FET (111). While the use of GCSF
seems promising in increasing EMT and possibly pregnancy
rates, most studies suffer from small sample sizes, and different
studies used different doses and time points when G-CSF was
administered, making interpretation rather difficult. Larger
8 Y. Mouhayar, F.I. Sharara
prospective, randomized, placebo-controlled, trials are there-
fore sorely needed.
The most promising evolving treatment modality in refrac-
tory cases appears to be stem cell therapy, as the administra-
tion of intrauterine angiogenic endometrial cells improved
the endometrial lining of patients with Asherman’s syndrome
or refractory thin lining. Murine models showed promising
results when bone marrow mesenchymal stem cells administra-
tion restored endometrial thickness to normal after total body
irradiation. Research is also developing to determine what
specific bone marrow-derived stem cell subtypes will have an
impact on endometrial regeneration. In an early human trials,
autologous bone marrow-derived stem cells gave promising
results in restoring endometrial thickness for a period of
6 months in patients with Asherman’s syndrome or refractory
thin endometrium, with excellent subsequent pregnancy rates,
making stem therapy a potentially valuable option for patients
who fail traditional treatment options (132,134). It is impor-
tant to note however, that stem cell therapy treatment is inva-
sive requiring a bone marrow biopsy and interventional
radiology assistance for injection into the uterine arterioles.
In conclusion, a receptive endometrium plays a critical role
in embryo implantation, and adequate endometrial growth is
essential to this process. Poor endometrial development is
associated with a decreased probability of pregnancy; yet, it
is not the sole predictor of pregnancy occurrence, and
endometrial pattern may be more critical. Among multiple
available treatment options, vaginal sildenafil during the stim-
ulation cycle appears to be a reasonable first line treatment
option, whereas intrauterine G-CSF infusion before ovulation
trigger could be a second line treatment option, provided
large randomized studies evaluating outcomes including when
is the best time point in a cycle (and at what dose) to admin-
ister G-CSF are performed. Stem cell therapy appears to be
promising in refractory cases; however, significantly more
research on safety, effectiveness, and cost, is needed before
this modality becomes adopted in the treatment of this frus-
trating condition.
Conflict of interest
The authors declared that there is no conflict of interest.
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