CLINICAL TRIAL

published: 14 February 2019

doi: 10.3389/fendo.2019.00061

Effect of Autologous Platelet-Rich

Plasma Treatment on Refractory Thin
Endometrium During the Frozen
Embryo Transfer Cycle: A Pilot Study
Hounyoung Kim, Ji Eun Shin, Hwa Seon Koo, Hwang Kwon, Dong Hee Choi and
Ji Hyang Kim*

Department of Obstetrics and Gynecology, Fertility Center of CHA Bundang Medical Center, CHA University School of
Medicine, Seongnam, South Korea

Edited by: Objective: Thin or damaged endometrium remains to be an unsolved problem in the
Jung Ryeol Lee, treatment of patients with infertility. The empirical preference for endometrial thickness
Seoul National University College of
(EMT) among clinicians is >7 mm, and the refractory thin endometrium, which doesn’t
Medicine, South Korea
respond to standard medical therapies, can be the etiology of recurrent implantation
Reviewed by:
SiHyun Cho, failure (RIF). Autologous platelet-rich plasma (PRP) is known to help tissue regeneration
Yonsei University College of Medicine, and is widely used in various fields. In the present study, we conducted PRP treatment
South Korea
Yodo Sugishita, and investigated its effect on the refractory thin endometrium.
St. Marianna University School
Design: Prospective interventional study (https://cris.nih.go.kr/cris, clinical trial
of Medicine, Japan
registration number: KCT0003375).
*Correspondence:
Ji Hyang Kim Methods: Women who had a history of two or more failed IVF cycles and refractory thin
bin0902@chamc.co.kr
endometrium were enrolled in this study. The main inclusion criteria were EMT of <7 mm
Specialty section: after more than 2 cycles of previous medical therapy for increasing the EMT. Twenty-four
This article was submitted to women were enrolled in this study. The subjects were treated with intrauterine infusion of
Reproduction,
a section of the journal
autologous PRP 2 or 3 times from menstrual cycle day 10 of their frozen-thawed embryo
Frontiers in Endocrinology transfer (FET) cycle, and ET was performed 3 days after the final autologous PRP infusion.
Received: 08 December 2018 22 patients underwent FET, and 2 patients were lost to follow up.
Accepted: 23 January 2019
Published: 14 February 2019
Results: The ongoing pregnancy rate and LBR were both 20%. The implantation
Citation:
and clinical pregnancy rates were 12.7 and 30%, respectively, and the difference
Kim H, Shin JE, Koo HS, Kwon H, was statistically significant. The average increase in the EMT was 0.6 mm compared
Choi DH and Kim JH (2019) Effect of
with the EMT of their previous cycle. However, this difference was not statistically
Autologous Platelet-Rich Plasma
Treatment on Refractory Thin significant. Further, EMT of 12 patients increased (mean difference: 1.3 mm), while that
Endometrium During the Frozen of seven patients decreased (mean difference: 0.7 mm); the EMT of one patient did not
Embryo Transfer Cycle: A Pilot Study.
Front. Endocrinol. 10:61.
change. There were no adverse effects reported by the patients who were treated with
doi: 10.3389/fendo.2019.00061 autologous PRP.

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Kim et al. Thin Endometrium Treatment With Platelet-Rich Plasma

Conclusions: The use of autologous PRP improved the implantation, pregnancy, and
live birth rates (LBR) of the patients with refractory thin endometrium. We assume that the
ability of autologous PRP to restore the endometrial receptivity of damaged endometrium
has some aspects other than increasing the EMT. The molecular basis of the treatment
needs to be revealed in future studies.
Keywords: refractory thin endometrium, platelet-rich plasma, recurrent implantation failure, frozen embryo
transfer, endometrial receptivity

INTRODUCTION used and investigated its effect on refractory thin endometrium

regarding the pregnancy and live birth rates.
Since the first introduction of in vitro fertilization and embryo
transfer (IVF-ET), the technology has evolved rapidly, and
the pregnancy rate with IVF-ET has significantly increased. MATERIALS AND METHODS
However, thin or damaged endometrium remains to be an Study Population and Inclusion Criteria
unsolved problem in the treatment of patients with infertility. We conducted an interventional prospective cohort study.
Several treatments to restore endometrial receptivity have been Patients were recruited from December 2015 to June 2017 in
attempted, including administration of exogenous estrogen, a fertility center of a university hospital. Women who had a
vitamin E, vaginal sildenafil citrate, and pentoxifylline (1–3). history of two or more failed IVF cycles and refractory thin
Patients with refractory thin endometrium who do not respond endometrium were enrolled in this study. The inclusion criteria
to the abovementioned treatment do not have many options, were as follows: (a) age of 20–45 years at the time of enrollment,
and an endometrium with a thickness below 7 mm is assumed (b) endometrial thickness (EMT) of <7 mm on the human
as non-optimal for embryo implantation and is associated with chorionic gonadotropin (hCG) administration day in fresh ET
a low pregnancy rate (4, 5). Recently, some progress in treating cycles or on the end of estrogen priming day in frozen ET cycles
damaged or thin endometria has been made with the use of in all of the previous cycles, (c) two or more failed IVF cycles,
the cell proliferation method, including stem cell therapy (6, 7). (d) more than two cycles of previous therapy for increasing
However, there are still unsolved issues concerning the safety and the EMT, such as, hysteroscopic adhesiolysis following hormone
usability of bone marrow-derived stem cells (8, 9). replacement therapy, high dose estradiol valerate, transvaginal
Autologous platelet-rich plasma (PRP) is one alternative sildenafil administration, or pentoxifyilline combination with
that is well-known for its safety. Such platelet products have vitamin E, (f) frozen embryo available for ET, and (g) informed
been used since the 1970s, and they have become more consent form signed. The exclusion criteria were as follows:
popular since the 1990s (10). Platelets are known as the blood (a) hematologic disorders, hemoglobin level of <9.0 g/dL or
component that plays a crucial role in hemostasis. During platelet count of <100,000/µL, (b) auto-immune disease, (c)
the healing process, growth factors, cytokines, and chemokines chromosomal abnormality in the patient or spouse, (d) peripheral
are secreted from the α-granules inside platelets. The various NK cell proportion of ≥12%, (e) body mass index (BMI) of
secreted proteins have paracrine effects on myocytes (11), ≥30 kg/m2 , and (f) uncontrolled endocrine or other medical
tendon cells (12), mesenchymal stem cells from different origins conditions, such as prolactinemia or thyroid diseases.
(13, 14), chondrocytes (15), osteoblasts (11, 16), fibroblasts
(17), and endothelial cells (18), stimulating cell migration, cell Autologous PRP Preparation
proliferation, and angiogenesis and consequently inducing tissue On each PRP administration day, 18 mL of venous blood was
regeneration (19). A study on a murine model was performed, drawn from the patients using 30 mL syringes coated with 2 cc
which reported that intrauterine infusion of autologous PRP of acid citrate A, anticoagulant solution (ACD-A; Arya Mabna
accelerated and enhanced regeneration of damaged endometria Tashkhis, Iran). The blood samples were then moved into an
and that the fibrosis within decreased (20). aseptic PRP centrifuge kit (PROSYS PRP; Prodizen, Korea) and
The first study on PRP for treating human thin endometrium centrifuged at 1017 G for 3 min. The buffy coat and plasma just
in vivo was published in 2015 (21). Four studies followed and above the buffy coat were collected, and 0.7–1.0 mL of PRP
concluded that PRP is a potent treatment for thin endometri um was produced and infused into uterine cavity. Based on the
(22–25). They stated that autologous PRP promotes endometrial data provided by the manufacturer, the platelet concentration of
growth and improves pregnancy outcomes. However, the PRP ranged from 717 × 103 to 1565 × 103 /µL, and the WBC
number of patients was small, and they did not provide sufficient concentration varied from 24,000 to 37,000/µL.
information on the type or concentration of PRP they used. It is
known that the efficacy of PRP can vary according to the platelet Autologous PRP Administration and ET
concentration and cell component (19, 26). In the present study, Intrauterine autologous PRP administration was performed at
we defined the platelet concentration and type of PRP that we the estrogen-primed FET cycle. The patients started to take a

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Kim et al. Thin Endometrium Treatment With Platelet-Rich Plasma

daily dose of 4–6 mg of estradiol valerate (Progynova; Bayer owing to personal reasons. Among the 22 patients who
Schering Pharma, France) from menstrual cycle day (MCD) 2 to underwent ET, two patients were lost to follow-up, and the data
prepare the endometrium. The first autologous PRP infusion was of the 20 remaining women were collected.
performed on MCD 10 and was repeated at 3 day intervals until The average age of the patients was 38.4 years. The mean
the EMT reached 7 mm. PRP was administered into the uterine duration of infertility in the 20 women was 5.7 years, and
cavity using an ET catheter within 1 h from completion of PRP the mean number of dilatation and evacuation performed
preparation. The syringe containing the PRP was connected to was 1.3. The mean number of failed IVF cycle was 2.7.
ET catheter and the PRP was infused. Then the syringed filled The mean EMT on the previous-cycle hCG administration
with the air was used to push in the remaining PRP. Then the or the final estrogen priming day was 5.4 mm. Sixteen of
air bubble was confirmed in ultrasonography. Thereafter, the them were diagnosed with endometrial sclerosis or adhesion
patients were prescribed with second-generation cephalosporin via hysteroscopy; the cause was radiation therapy for treating
for 2 days as prophylaxis for infection. The maximum number of colon cancer in one patient and pelvic tuberculosis in another
autologous infusions was limited to three. patient (Table 1).
Ultrasonography was performed to measure the EMT on
MCD 2 and every autologous PRP administration day until
ET. ET was conducted 3 days after the final autologous PRP Treatment Outcome
administration. Luteal phase support was performed using The number of embryos transferred in each patient was 2 or
either 90 mg of vaginal progesterone (Crinone gel 8%; Merck, 3. The cleavage stage embryo grading was performed using the
Germany) or 50 mg of progesterone (Sugest Inj. 50 mg; Uni- qualification scale by Veeck (27). The blastocysts were graded
Sankyo, India) administered via intramuscular injection daily using the Gardner grading system (28). A good-grade embryo
from 3 days before the ET day. The serum β-hCG level was was defined as a grade I or II cleavage stage embryo with six or
measured from peripheral blood 2 weeks after ET. Those with more cells and blastocyst score of 3BB or higher. The morula was
positive β-hCG results underwent ultrasonography another 2 considered as a good-grade embryo. Seventeen patients had at
weeks later to confirm clinical pregnancy. Clinical pregnancy was least one good-grade embryo; however, three patients had only
defined as the presence of intrauterine gestational sac. The luteal poor-grade cleavage embryos.
phase support was continued until 9 weeks of pregnancy. The The gestational sac was confirmed in 30% (n = 6) of the
obstetric progress of the pregnant patients was followed up via patients. One patient had missed abortion at 8+2 weeks of
a timely chart review. gestational age. Another patient had heterotopic pregnancy,
and the intrauterine fetus was aborted at 6 weeks soon after
Comparison of the Outcomes Between the laparoscopic removal of the ectopic conceptus. The live birth
Treatment and Previous Cycles rate was 20% (n = 4). All the ongoing pregnancies resulted
The variables of the most recent ET cycles were compared in live births without obstetric complications. The mean EMT
with those of the treatment cycle. The primary outcomes were after the PRP treatment was 6.0 mm. The average increment
the ongoing pregnancy rate and LBR. The secondary outcomes in the EMT was 0.6 mm. However, this difference was not
were the implantation rate, clinical pregnancy rate, and EMT statistically significant. Individually, the EMT of 12 patients
increment compared with those on the previous cycle. increased (mean difference: 1.3 mm), while that of seven patients
decreased (mean difference: 0.7 mm); however, the EMT of
Data Analysis one patient did not change. Among the six clinical pregnancy
The statistical analysis was performed using the IBM SPSS R cases, two were increased and four were decreased in EMT
software, version 24 (IBM Corporation, Armonk, NY, USA). (Figure 1). There were no adverse effects reported by the
Wilcoxon signed-rank test was used to compare the differences patients. The outcomes of the treatment are summarized
between the pre-PRP and post-PRP EMT. A P value of < 0.05 was in Table 2.
considered statistically significant. The implantation rate, clinical
pregnancy rate, and live birth rate were analyzed using Fisher’s
exact test. Comparison of the Outcomes Between the
Treatment and the Previous Cycles
Ethics Approval The treatment cycle outcomes were compared with the most
This study was approved by the Institutional Review Board recent ET cycle outcomes of each patient; the latter cycle
committee of Bundang CHA Medical Center. was considered as the control cycle. The implantation, clinical
pregnancy, and live birth rates in the treatment cycle were 12.7,
RESULTS 30, and 20%, respectively. The implantation, clinical pregnancy,
and live birth rates in the control cycle were all 0%. The
Study Population and Baseline implantation and clinical pregnancy rates were significantly
Characteristics higher in the treatment cycle than in the control cycle. The
A total of 24 women were recruited, and 22 of them underwent age, BMI, number of transferred embryos, and number of good-
ET. One patient underwent preimplantation genetic screening, grade embryos transferred were not significantly different. The
and all embryos were abnormal. Another patient had withdrawn comparison results are summarized in Table 3.

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Kim et al. Thin Endometrium Treatment With Platelet-Rich Plasma

TABLE 1 | The baseline characteristics of the patients.

Age BMI (kg/m2 ) Infertility No. of Failed IVF Infertility Parity# Hystero- Medical EMT (mm),
Parameters factor D&E cycles duration scopic history On previous
Patient no. (years) finding cycle hCG
day or final
T P A L
priming day

1 31 20.1 Tubal, IUA 0 2 3.1 0 0 0 0 IUA Past 5.8

Tuberculosis
2 35 28.4 Tubal, IUA 4 2 6 0 0 4 0 Synechia 4.8
3 39 20.7 IUA 2 2 7.1 0 0 2 0 Central IUA 6.7
4 40 23.6 Tubal DOR 3 2 10.5 0 0 3 0 Erythematous 6.0
IUA EM
5 30 17.7 MF, IUA 1 2 1.9 0 0 1 0 No specific Past PID 6.4
6 34 22.3 Tubal, IUA 0 3 6 0 0 0 0 Severe IUA 4.9
7 45 25.3 DOR, 1 3 8 0 0 1 0 No specific 5.2
8 33 22.4 IUA 1 2 3.7 0 0 1 0 Synechia 5.5
9 35 22.3 Tubal, IUA 0 4 6.5 0 0 1 0 Severe IUA 4.9
10 36 20.8 IUA 1 5 8.5 0 0 1 0 Synechia 5.5
11 37 21.3 POI, IUA 0 2 3.3 0 0 0 0 Severe IUA Past RT 4.0
(colon ca.)
12 38 25.4 unexplained 0 2 10 0 0 1 0 No specific 4.8
13 39 26.0 unexplained 1 4 4 0 0 1 0 Sclerotic EM 5.8
14 39 28.6 SM myoma, 0 3 5 1 0 0 1 Synechia 6.8
PGD
15 41 24.0 IUA, MF 0 4 4.3 0 0 0 0 Severe IUA 4.3
16 41 20.6 IUA 3 2 1.5 0 0 3 0 Synechia 5.3
17 43 28.6 DOR IUA 5 2 6.6 0 0 5 0 Septum c 5.7
fistula
18 43 19.2 IUA 1 2 5.7 1 1 2 1 Sclerotic 4.5
fundus
19 44 22.4 MF, IUA 2 3 9 0 0 2 0 Sclerotic walls 6.5
20 44 25.7 DOR 0 2 2.4 2 0 0 2 Synechia 5.4
Mean ± SD or explanation 38.4 ± 4.3 23.3 ± 3.1 1.3 ± 1.5 2.7 ± 0.9 5.7 ± 2.6 17 primary 16 patients – 5.4 ± 0.8
3 secondary with
endometrial
pathology

EMT, endometrial thickness; hCG, human chorionic gonadotropin; RT, radiation therapy; IUA, intrauterine adhesion; DOR, diminished ovarian reserve; POI, primary ovarian insufficiency;
MF, male factor; SM, submucosal; D&E, dilatation and evacuation; T, term birth; P, preterm birth; A, Abortion; L, living birth. # The abortion count of parity includes chemical abortion.

DISCUSSION of the five studies. Table 4 summarizes the five previous studies
on PRP for treating patients with repeated implantation failure
The purpose of the present study was to determine whether owing to endometrial factors.
intrauterine administration of PRP would improve the pregnancy Although PRP is widely applied in different clinical areas,
outcomes of patients with refractory thin endometrium. A total the procedure in preparing PRP is not yet standardized.
of 20 women were enrolled, and a clinical pregnancy rate of Therefore, the platelet quantification and growth factor contents
30% and a live birth rate of 20% were achieved in these patients are not defined (19). The previous studies did not present
with poor prognosis. However, contrary to the expectation, even critical information on the PRP used, such as cell contents,
the mean EMT increased after treatment, and there was no platelet concentration, and activation. We attempted to provide
association between the EMT changes and the ET outcomes. information on PRP and its preparation method and searched
Since the first study on in vivo autologous PRP on the human for the best-known evidence to improve the effectiveness of
endometrium in 2015, five studies have been published (21–25). PRP. The optimal biological effect seems to occur when PRP
The inclusion criteria differed to some extent; however, all studies with a platelet concentration of approximately 1,000,000/µL
showed that autologous PRP is effective in repairing the damaged (503,000–1,729,000/µL) is used. At lower concentrations, the
endometrium and improving the pregnancy outcomes. The LBRs effect is suboptimal, while higher concentrations might have
reported by three studies were all above 25%. The autologous PRP a paradoxically inhibitory effect (29). We employed a PRP
preparation method and cell contents were not reported in three preparation method using an aseptic PRP preparation kit that

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Kim et al. Thin Endometrium Treatment With Platelet-Rich Plasma

FIGURE 1 | Pre- and post- endometrial thickness of each patient. The color of the line indicates the obstetric result of the patient.

TABLE 2 | The results of autologous platelet-rich plasma treatment.

Pat. No. Obstetric result EMT Final (mm) Embryo grade and number β-hCGU No. of G sac

Week Result AVG

1 37+5 Live birth 5.7 6.4 10C GIII, 8C GI + 1

2 38+6 7.1 Mor, 12C GII x 2. + 1
3 38+3 5.6 Mor, 12C GI, 8C GI + 2*
4 37+2 7.3 Mor, 12C GI, 10C GIII + 1

5 8+2 Abortion 5.8 5.0 Mor, 10C GIII + 1

6 6 4.2 Mor, 12C GII, 12C GIII + 1‡

7 5 Chemical pregnancy 5.5 5.5 12C GII, 10C GI, 6C GIII + 0

8 Not-pregnant Not-pregnant 6.4 6.1 12C GI, 10C GI – N/A

9 3.8 Mor x 2, 12C GII –
10 4.9 12C GIV, 10C GIII, 10C GIV –
11 5.4 8C GII, 6C GIII, 4C GIII –
12 5.4 6C GIV x 2 –
13 6.0 Mor, 12C GII, 10C GIII –
14 6.3 Mor x 2, 8C GIV –
15 7.1 8C GIII, 7C GIII, 6C GIII –
16 6.3 Mor x 2, 10C GIII –
17 5.7 12C GII, 12C GIII, 8C GI –
18 6.3 Mor, 8C GII, 4C GI –
19 9.1 Mor, 10C GII, 6C GIII –
20 6.2 Mor x 2, 10C GIII –

Average/ Full term: 4 LBR: 20% 6.0 ± 1.6 7 patients (35%) 6 patients
counts patients (20%) ABR: 15% (35%) (30%)

EMT, endometrial thickness; Mor, Morula; hCG, human chorionic gonadotropin; G sac, gestational sac; LBR, live birth rate; ABR, abortion rate; U β-hCG cut off: 35 mIU/mL, * Vanishing
twin, ‡ Missed abortion after laparoscopy for heterotopic pregnancy.

had manufacturer’s information on the platelet count of the final There are four categories of platelet concentrate preparations:
product as 717,000 to 1,565,000/µL and the WBC concentration leukocyte-poor or pure PRP (P-PRP), leukocyte PRP (L-PRP),
as 24,000 to 37,000/µL. pure platelet-rich fibrin clot, and leukocyte platelet-rich fibrin

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Kim et al. Thin Endometrium Treatment With Platelet-Rich Plasma

TABLE 3 | Comparison of outcomes between the treatment and the previous per Applebaum grading) of the endometrium.” The patients of
cycles. our study had at least 2 failed previous IVF cycles and had no
Parameters / cycle Previous Treatment P-value
improvement in endometrial thickness after two or more cycles
Cycle Cycle of medical therapies. The average of infertile period was 5.7
years and more than 2/3 of them had intrauterine adhesion from
Age 37.6 ± 4.4 38.4 ± 4.3 0.547 hysteroscopic findings.
BMI (kg/m2 ) 22.89 ± 3.2 23.3 ± 3.1 0.640 The EMT was reported to have increased after PRP treatment
EMT on hCG triggering or 5.4 ± 0.8 6.0 ± 1.1 0.070 in the previous studies. In the present study, the average increase
final preparation day* (mm) in the EMT was 0.6 mm. However, this difference was not
Cycle types (fresh/frozen) 10/10 0/20 statistically significant. Furthermore, there was no correlation
Number of transferred 2.6 ± 0.7 2.8 ± 0.4 0.640 between the EMT increase and pregnancy outcomes. Among
embryos
the six clinical pregnancy cases, two were increased, and four
Number of good quality 1.7 ± 0.8 1.7 ± 0.9 0.967
were decreased in EMT. A study examining the pregnancy
embryos transferred
outcomes of euploid ET (35) and a systemic review with meta-
Implantation rate (%) 0 (0/52) 12.7 (7/55) 0.015
analysis on the EMT as a prognostic factor of pregnancy (36)
Clinical pregnancy rate (%) 0 (0/20) 30 (6/20) 0.020
reported that the EMT was not significantly associated with the
Ongoing pregnancy rate (%) 0 (0/20) 20 (4/20) 0.106
pregnancy outcomes. Accordingly, we assumed that autologous
Live birth rate (%) 0 (0/20) 20 (4/20) 0.106
PRP intrauterine administration improved the endometrial
EMT, endometrial thickness; hCG, human chorionic gonadotropin. *EMT on hCG receptivity of the patients with refractory endometrium through
triggering day in fresh cycles and on final preparation day in frozen-thawed cycle. the way that cannot be checked by EMT.
There was no difference in other clinical characteristics
including age, infertility duration, number of failed IVF cycles,
clot. Among them, two families contain a significant number and transferred embryo number and grade according to
of leukocytes. P-PRP and pure platelet-rich fibrin clot are made pregnancy outcomes. Therefore, there is no prognostic factors
without the buffy coat and considered to contain a minimal expecting successful results in PRP treatment. However, this
amount of leukocytes (30). The variety of PRP preparations result might be due to small number of cases and further
currently available on the market has led to considerable study with larger number of subjects is necessary to confirm
confusion in the evaluation of the potential clinical benefits of this finding.
PRP in different applications (26). The advantage of each type of Endometrial receptivity is controlled by dynamic and
PRP in specific tissues has not been defined yet. precise molecular and cellular events of cytokines, homeobox
Two of the previous studies (21, 25) provided information transcription factors, and genes (37). Of the cytokines, leukemia
that they used the buffy coat of the centrifuge, and this implies inhibitory factor (LIF) has been found to have a role in uterine
that they employed L-PRP. There are conflicting opinions on the preparation and embryo attachment (38, 39). Lif -deficient female
leukocyte content in PRP. One view is that leukocytes increase mice showed an implantation failure and were rescued with
inflammation and reduce tissue regeneration (31). Another view LIF supplementation (40, 41). PRP treatment upregulates LIF
is that inflammation is an essential step in the healing process expression in endometrial stromal cells (42), and upregulated
(32), especially for protection against infection and clearance LIF expression could enhance endometrial receptivity. It is
of tissue debris (33). There was also a recent study by Cousins also suggested that PRP may exert some effect to enhance the
et al. that provided evidence that mononuclear phagocytes have placentation of trophoblasts. Amable et al. showed that the levels
roles in scar-less endometrial healing in menstrual cycles (34). of 12 proteins increased in activated PRP in comparison with
We also used the buffy coat of the centrifuge, and thus, L- whole blood plasma or platelet-poor plasma. Six growth factors
PRP was employed. The leukocytes in PRP could have increased (i.e., PDGF-AA, PDGF-AB, PDGF-BB, TGF-β1, TGF-β2, and
inflammation; however, the implantation and pregnancy rates EGF), three anti-inflammatory cytokines (i.e., IL-4, IL-13, and
improved. Since no studies have stated the use of P-PRP, its IFN-α), and three pro-inflammatory cytokines (i.e., IL-8, IL-17,
effectiveness needs to be explored in the future. and TNF-α) were included (19). These cytokines and growth
LBR was reported in two of the previous studies (23, 24). factors may increase endometrial receptivity. The vascularity of
The first study reported 26.3% of live birth after PRP treatment the endometrium increased in the study by Tandulwadkar et al.
and the LBR of the second study was 38.2%. The difference The endometrial vascularity measured using power doppler after
of LBR between the previous and the present studies may be PRP treatment significantly increased, especially in the group
caused by the difference in patient characteristics. The inclusion that achieved pregnancy after PRP treatment (24). More studies
criteria of the first study was “aged between 33 and 45 years with on the molecular basis of PRP treatment are required to reveal
a previous history of refractory endometrium and at least one the exact mechanism and to specify which group of patients
failed IVF attempt” and the second study criteria was “between would benefit the most from the autologous PRP treatment of
22 and 40 years of age with a suboptimal endometrial pattern, the endometrium.
as identified by ET <7 mm despite standard dose of estradiol Prevention of intrauterine adhesion after curettage or
valerate, or suboptimal endometrial vascularity, defined as <5 hysteroscopic operation of myoma or endometrial polyp is
vascular signals reaching the central zone (zones 3 and 4 as a good candidate for endometrial PRP treatment. However,

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Kim et al. Thin Endometrium Treatment With Platelet-Rich Plasma

TABLE 4 | Previous studies on autologous PRP treatment of human endometrium.

References Patients PRP preparation Result and Conclusion

No HRT on PRP EMT β- hCG On-going Live Missed

FET repeat pregnancy birth Ab

Chang et al. 5 Yes 2 L-PRP >7 mm 5 (100%) 4 (80%) Not 1 (20%)

(21) No information on (100%) reported
platelet
concentration
EMT < 7 mm on previous PRP promote endometrial growth and improve
hCG day despite HRT pregnancy outcome
Zadehmodarres 10 Yes 2 L-PRP >7 mm 5 (50%) 4 (40%) Not –
et al. (25) No information on (100%) reported
platelet
concentration
EMT < 7 mm 4 patients PRP is effective for endometrium growth
were diagnosed as
intrauterine adhesion by
HSC
Molina et al. 19 Yes 2 No information on >9 mm 15 5 (26.3%) 5 1 (.26%)
(23) PRP preparation (100%) (73.7%) (26.3%)
method, platelet
concentration or
WBC’s in PRP
history of the refractory PRP seems beneficial for endometrial
endometrium with at least 1 microvasculature and endometrial receptivity of the
failed previous IVF cycle refractory endometrium
Colombo 8 – – No information >6.5 mm 6 4 (57%) 2 1
et al. (22) (88%) (85.7%) (28.5%) (14.3%)
more than 3 canceled FET Inefficient expression of adhesion molecules can be
d/t EMT < 6 mm HSC: no replaced by PRP
EM pathology
Tandulwadkar 68 Yes 2 No information on Average 39 31 (45.3%) 26 5
et al. (24) platelet 7.22 mm (60.9%) (38.2%) (7.35%)
concentration or
WBC’s in PRP
suboptimal endometrial Endometrial vascularity measured with power
growth; thickness<7 mm or Doppler was increased
<5 vascular signals
reaching central zone

EMT, endometrial thickness; hCG, human chorionic gonadotropin; MCD, menstrual cycle day; HRT, hormonal replacement therapy; FET, frozen-thawed Embryo Transfer; HSC,
hysteroscopy; L-PRP, Leucocyte-platelet rich plasma.

concerns have been raised regarding PRP use for regeneration rate in IVF-ET. In a recent large-scale prospective randomized
or reconstruction on cancer tissue removal site because PRP clinical trial (RCT), Shi et al. reported that there is no significant
contains and induces various growth factors and cytokines to difference in the pregnancy outcomes between fresh and frozen
promote cell proliferation and regeneration. There have been embryos when transferred to ovulatory women (47). Further, a
a few clinical studies reporting favorable outcomes of using meta-analysis including four RCTs also showed that there is no
PRP in breast reconstruction after mastectomy in breast cancer clear evidence on the difference in the cumulative pregnancy
patients (43, 44). However, there is no study on endometrial rates between fresh and frozen-thawed ET cycles (48). In the
PRP treatment after curettage in endometrial cancer patients. present study, 14 of the 20 patients have undergone FET in the
Although in vitro studies reported that the growth factors and previous cycles, and all the cycles failed to achieve pregnancy.
VEGF of PRP could promote cancer recurrence (45, 46), the role Among the six pregnant cases after the PRP treatment, three
of PRP in tumor proliferation and recurrence in cancer patients underwent fresh ET, and the other three underwent FET as the
yet needs further investigation. control cycle. Therefore, we assumed that the difference in the
In the present study, the PRP treatment was performed during transfer cycle characteristics (fresh vs. frozen) would not affect
the FET cycle; however, half of the most recent cycles that were the outcomes significantly in our study.
used as control cycles were conducted during the fresh cycle. There are limitations in this study. First, the study population
It is still controversial whether FET increases the pregnancy was small to show a statistically significant result on live birth

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Kim et al. Thin Endometrium Treatment With Platelet-Rich Plasma

rate. The live birth rate was 20% in the treatment cycles, on the beneficial effect of PRP on the endometrium of
but was not significantly increased compared with that in various pathophysiology.
the control cycles showing no pregnancy. A follow-up study
consisting of larger number of patients is necessary and is AUTHOR CONTRIBUTIONS
actually currently being performed. Second, this study was not
an RCT; thus, the effectiveness of the PRP treatment was shown HKi: collection, analysis, and interpretation of data, drafting, and
only by comparison with the most recent previous cycle of revision of the manuscript; JS, HKo, HKw, and DC: conception
each patient. and design, data interpretation, and revision of the manuscript;
The present study was conducted as a pilot study to determine JK: conception and design, data analysis, data interpretation,
the effects of autologous PRP treatment on refractory thin revision and final approval of the manuscript.
endometrium. The implantation, clinical pregnancy and live
birth rates reached up to 12.7, 30, and 20%, respectively. This FUNDING
result is a noticeable improvement considering the patients’
history. Further studies on the molecular basis of this PRP This research was supported by a grant of the Research Driven
treatment and well-designed RCTs are necessary to reveal Hospital R&D project, funded by the CHA Bundang Medical
the exact mechanism and to obtain more solid evidence Center (grant number :BDCHA R&D 2015-47).

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