Recent evidence based tips to improve endometrial thickness for assisted reproductive technology

1. Dr. Poonam Loomba M.D.
MANAGEMENT OFTHIN
ENDOMETRIUM
Dr Poonam Loomba ,M.D.

2.  The endometrium, derived
from the mucosal lining of the
fused müllerian ducts, is
essential for reproduction and
may be one of the most
complex tissues in the human
body. It is always changing,
responding to the cyclic
patterns of estrogen and
progesterone of the ovarian
menstrual cycle, and to a
complex interplay among its
own autocrine and paracrine
factors.

3.  Upper two-thirds “functionalis” (stratum compactum
and stratum spongiosum) layer
 Lower one-third “basalis” layer.
 Functionalis layer prepares for the implantation of the
blastocyst and, therefore, it is the site of proliferation,
secretion, and degeneration.
 Basalis layer provides the regenerative endometrium
following menstrual loss of the functionalis.
(Speroff clinical gynecologic endocrinology 9th edition)

4.  Assisted reproductive
technology has
grown by leaps and
bounds in the last
few years
 India has recorded
the biggest growth
in ART centers &
no. of ART cycles
performed every
year
Year 2000
5500 cycles
Year 2006
21,500
cycles
Year 2011
1,10,000
cycles
IVF-ICSI cycles in India
J Hum Reprod Sci. 2013 Oct-Dec; 6(4): 235–240.
Very soon India will be the
leader in the world of ART in terms of a
number of cycles.

5.  Thickness
 Pattern
 Blood flow to the endometrial and
subendometrial zone
 Volume

8.  The cost per cycle, is between 1,00,000 to 2,00,000 which is in
addition to the subsequent obstetric costs
70-80%
Failure
A take-home baby rate of
just 20-30%
Thus,
IUI success rates
5 to 20%

9. Nonreceptive
endometrium
Adversely affect the cross-talk
between embryo & the
endometrium
Fertility and Sterility®Vol. 97, No. 5, May 2012 0015-0282
Various studies have taken it as < 6mm , < 7mm
and sometimes < 8mm. 7mm is most accepted
although pregnancies have been reported at very
thin endometrium as well.

10. Mean
endometrial
thickness
Mean
endometrial
thickness
CONCLUSION:
J Hum Reprod Sci. 2011 Sep-Dec; 4(3): 130–137.
The mean endometrial thickness was significantly
higher in pregnant women as compared to non-
pregnant women

11. Blood supply to the
endometrium
&
Endometrial thickness
Thin endometrium is
characterized by
 high-flow impedance of
uterine radial artery
 poor epithelial growth
 decreased expression of
vascular endothelial growth
factor
Poor vascular development
Journal of SouthAsian Federation of Obstetrics and
Gynaecology, April-June 2018;10(2):81-83
. Pathophysiologiy of "thin" endometrium.
Miwa I1,Tamura H,Takasaki A,YamagataY, Shimamura K, Sugino
Fertil Steril. 2009 Apr;9

12.  Iatrogenic: injuries to the endometrial layer can happen during
the course of D&C, myomectomy, caesarean section,
polypectomy etc. Difficult for the endometrium to grow again if
the basalis layer is damaged
 Inflammtory: Tuberculosis of the endometrium, chronic bacterial
infections, sexually transmitted infections and pelvic
inflammatory diseases can lead to permanent scarring of
endometrium.
 Other causes:
 Low estrogen levels
 Use of CC
 Prolonged use of progesterone and COCs
 Inadequate blood flow
 Systemic causes (HTN, Diabetes, asthma, substance abuse like
smoking etc.)
 Idiopathic
https://www.indianfertilitysociety.org/pdf/ARText5-ThinEndometrium.pdf?

14. Earlier
options
Hormonal adjustment
Pentoxifylline &Tocopherol
Low dose aspirin
Acupuncture
L-arginine
Nitroglycerine patch
Recent
agents
Vaginal Sildenafil
Granulocyte colony-
stimulating factor
Stem cell therapy
Endometrial scratch
Platelet rich plasma
Journal of SouthAsian Federation of Obstetrics and Gynaecology, April-June 2018;10(2):81-83

15.  Endometrial proliferation is dependent on serum
estrogen levels

 Tourgeman et.al. (2001) demonstrated that the
extended use of vaginal E2 (from 4 to 6 weeks) was
successful in achieving adequate endometrial lining
 In 2015, Liu et al concluded that it is the duration of
estrogen administration and not the serum
concentration that matters.
 Vaginal route can be tried if oral administration fails.

16.  JanKe H et.al.2017-showed that tamoxifen protocol
improves EMT in patients after NC, HRT, and OI
cycles
 With CC adequate follicular recruitment but thin
endometrium (<7 mm), switching to tamoxifen in
subsequent cycles improves endometrial thickness.
Kassey R.et.al. 2010
 It may not be a first-line treatment in patients with
adequate endometrium but may be a promising
alternative for patients with thin endometrium.

17.  Qublan et al :
 60 patients were given 0.1mg Triptorelin on
day of egg pu, ET and 3 days after ET
 60 Patients served as control group
 There was significant increase in ET and
pregnancy rates in study group.

18.  HCG endometrial priming for 7 days in the
proliferative phase with estrogen in frozen
cycles seems highly promising. (Papanikolou Et Al in
2013)
 Robab Davar et.al. in 2016 concluded that HCG
priming of endometrium leads to significant
improvement in thickness and pregnancy
outcome.
 150 iu hcg from day 8 till day 14 or 15 along with
estrogens in FET and Donor egg cycles.

19. Tocopherol (vitamin E) is a potential anti-oxidant and scavenges
reactive oxygen species (ROS) at times of oxidative stress.
Takasaki et al. (2010) Cicek N et al. (2012) concluded thatVit E
administration may improve the endometrial response in
unexplained infertile women via the likely antioxidant and the
anticoagulant effects
 Mechanism of action of PTX resulting in better development of
endometrium is that it causes vasodilation and also decreases
inflammation.
 Combination of tocopherol 1000 IU and pentoxyphylline 800mg
x 6 to 9 months has been reported to be useful in radiation
induced fibrosis in experimental model and in humans (Delanian
et al., 2003)
Journal of SouthAsian Federation of Obstetrics and Gynaecology, April-June 2018;10(2):81-83

20. The mechanism explaining the role of low-dose aspirin is that it
decreases the pulsatility index of the uterine artery and thus increases
the blood flow to the endometrium.
Cochrane review in 2010 (Glujovsky D et.al.) found no benefit in adding
aspirin for endometrial preparation.
Wang et.al. in 2017 included thirteen randomized controlled trials with
3104 participants.
There were no significant differences in implantation rate, live birth
rate ,miscarriage rate ,fertilization rate and endometrial thickness but
it showed that aspirin treatment may slightly improve the clinical
pregnancy rate (RR = 1.16; 95% CI = 1.04-1.28) compared to placebo or
no treatment

21.  One of the oldest interventions of traditional Chinese
medicine
 Electroacupuncture decreases the uterine artery blood flow
resistance and thus increases the blood flow
 Better growth without a significant difference in pregnancy
rates
Journal of SouthAsian Federation of Obstetrics and Gynaecology, April-June 2018;10(2):81-83

22.  A nitric oxide donor and relaxes vascular smooth muscles of
endometrium
 it has been shown to decrease the resistive index.
 In a pilot study, 9 patients who showed a thin endometrium in the
late follicular phase were given l-arginine (6 g/day, orally)
 L-arginine treatment improved EM in six (67%) out of nine
patients, and one patient conceived.
 Many more trials are needed before L arginine can be used for thin
endometrium.Journal of SouthAsian Federation of Obstetrics and Gynaecology, April-June 2018;10(2):81-83
.Takasaki Aet al FertilSteril. 2010 Apr; 93(6): 1851-812
https://www.indianfertilitysociety.org/pdf/ARText5-ThinEndometrium.pdf?

23.  It improves the uterine blood flow, but it is associated with
side effects like headache and hypertension.
 Largest controlled clinical trial suggested that , the
treatment with nitroglycerine patch did not improve Doppler
parameters even among the women with poor uterine
perfusion before treatment.
 Similar findings have also been reported when transdermal
10 mg NTG was administered to pregnant patients with
impaired uterine perfusion
Human Reproduction,Volume 17, Issue 10, 1 October 2002
Journal of SouthAsian Federation of Obstetrics and Gynaecology, April-June 2018;10(2):81-83

24. Benni & Patil; Indian J Health Sci 2016;9:131-6.

25. Supporting use of
VAGINAL Sildenafil for Improving
Endometrial thickness

26. Human Reproduction 2000;15(4):806-809
Vaginal Sildenafil citrate decreases pulsatility index and thus improves
uterine blood flow and endometrial development

27.  The PI ranged between 2.0 and 3.4 which decreased to between 1.5 and
2.7 after 7 days of sildenafil (reflecting increased diastolic blood flow)
 The endometrial thickness developed to >10 mm in these patients after 7
days
 Significant number of patients were successfully conceived
Vaginal Sildenafil is effective for improving uterine artery blood flow
and endometrial development in IVF patients with prior poor
endometrial response
Human Reproduction 2000;15(4):806-809

28. Fertility & Sterility.2010;93:1851-8
Study design:
Prospective observational study
n=12
Sildenafil
100mg/d
intravaginal
ly
56 patients with thin endometrium
(ET<8mm) & high radial artery-
resistance index of ᴜRA (RA-
RI≥0.81)
n=25
Vit.E
600mg/
d
n=9
L-
arginine
6g/d
n=10
contro
l
Sildenafil
in women with thin
endometrium

29. Sildenafil citrate, Vit.E, L-arginine treatment improves high radial
artery-resistance index (RA-RI) & endometrial thickness and may
be useful for patients with thin endometrium
Fertility & Sterility.2010;93:1851-8
Conclusion
No side effects were reported

30. Vaginal Sildenafil citrate and CC improves endometrial thickness (11.8
mm) vs CC alone (10.2 mm) in infertile women

31. Fertil Steril. 2002 Nov;78(5):1073-6
Vaginal Sildenafil citrate enhances endometrial thickness >9 mm in patients with IVF
failures attributed to inadequate endometrial development

32. Vaginal Sildenafil
citrate increases
endometrial
thickness without
systemic side
effects

33. Effect of Oral Sildenafil in Indian patients

34. Iran J Reprod MedVol. 11. No. 2. pp: 151-158, February 2013
Oral Sildenafil
improves triple
line patterns,
endometrial
thickness and
endometrial
receptivity

35. Sildenafil vaginal gel significantly increased endometrial thickness and uterine
blood flow, and may improve pregnancy rate in patients with CC failure due to thin
endometrium.
FactsViewsVis Obgyn, 2017, 9 (1): 21-27

36. Oral Sildenafil citrate in elderly
patients (>40 years) shows 9.4 mm
endometrial thickness with 31.1%
pregnancy rate
Fertility and Sterility;Volume 84, Supplement 1, Page S246, September 2005

37. For Increasing EndometrialThickness and as support in ovulation Induction
Time of Cycle Dose Duration
Follicular phase 25 mg SildenafilTID Day 2 till Day 10 OR
Day 7 to Day -12
Luteal Phase 25 mg SildenafilTID Day 13 till HCG /FET
trigger

38.  G-CSF, initially described as a hematopoietic growth factor
 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)
 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
Middle East Fertility Society Journal (2017) 22, 1–12

39.  Eighty-two patients were diagnosed with thin endometrium (<7 mm).Thirty
patients with previously cancelled embryo transfers received intrauterine G-CSF
in subsequent frozen embryo transfer (FET) cycles.
 Divided into the G-CSF only and G-CSF with endometrial scratch subgroups
.
 Compared with previous cycles, endometrial thickness increased from 5.7 ±
0.7 mm to 8.1 ± 2.1 mm after G-CSF treatment (P < 0.001). Endometrial thickness
increases were not significantly different between the two subgroups.
 The G-CSF with endometrial scratch subgroup established nominally higher
though non-significant clinical pregnancy and live birth rates than the G-CSF only
subgroup .
 Endometrial scracth did not impair G-CSF treatment for thin endometrium and
favoured pregnancy and live birth rates. For patients with thin endometrium,
embryo transfer cancellation and G-CSF treatment in subsequent FET cycles is
beneficial.

40.  CONCLUSION(S):
 In normal IVF patients, G-CSF does not affect
endometrial thickness, implantation rates, or
clinical pregnancy rates. Because these
results were obtained in an older patient
population, they may not necessarily apply to
younger women.
 Fertil Steril. 2014 March

41.  PARTICIPANTS/MATERIALS, SETTINGS AND METHOD:
 This study was uncontrolled, each patient serving as her own
control in a prospective evaluation of endometrial thickness.The
mean ± SD age of the cohort was 40.5 ± 6.6 years, gravidity was
1.8 ± 2.1 (range 0-7) and parity was 0.4 ± 1.1 (range 0-4); 76.2% of
women had, based on age-specific FSH and anti-Müllerian
hormone, an objective diagnosis of diminished ovarian reserve
and had failed 2.0 ± 2.1 prior IVF cycles elsewhere.
 WIDER IMPLICATIONS OFTHE FINDINGS:
 This pilot study supports the utility of G-CSF in the treatment of
chronically thin endometrium and suggests that such treatment
will, in very adversely affected patients, result in low but very
reasonable clinical pregnancy rates.

42.  RESULTS:
 Endometrial vascularity in the intervention group was significantly higher
on the day of embryo transfer compared to the placebo group. Clinical
pregnancy rate was 27.6% in the intervention group compared to 18.9%
in the placebo group and the difference was not statistically significant
(P = 0.207).There was no statistically significant difference between
biochemical pregnancy rate, implantation rate, ongoing pregnancy rate,
live birth rate and endometrial parameters between the two groups
.
 CONCLUSIONS:
 Routine use of G-CSF in unselected IVF cycles may not lead to increase in
positive IVF outcomes. More trials with larger sample sizes are required
before approving or refuting the role of routine G-CSF in increasing IVF
success rates.

43.  METHODS:
 A review of the scientific literature related to patients with thin
endometrium undergoing fertility treatment.
 RESULTS:
 We specifically reviewed two relatively new treatment options for
resistant thin lining: intrauterineG-CSF and stem cell therapy.The
majority of the reviewed trials showed a significant benefit for
intrauterine G-CSF infusion in improving endometrial thickness and
pregnancy rates. Early results of stem cell therapy trials seem promising.
 CONCLUSIONS:
 Intrauterine G-CSF infusion appears to be a potentially successful
treatment option for resistant cases, while stem cell therapy seems to be
a promising new treatment modality in severely refractory cases.

44.  A total of 62 women with thin unresponsive endometrium were included in
the study, of which, 29 received a G-CSF infusion and 33 who opted out of the
study served as controls. Patients in both groups had similar endometrial
thickness at the time of the initial evaluation: 6.50 mm (5.50-6.80) in the G-
CSF and 6.40 mm (5.50-7.0) in the control group
 The live birth rate was 2/29 (6.89%) in the G-CSF group and 2/33 (6.06%) in
the control group (p>0.05).
We concluded that G-CSF infusion leads to an improvement in endometrium
thickness but not to any improvement in the clinical pregnancy and live birth
rates. Until more data is availableG-CSF treatment should be considered to
be of limited value in increasing pregnancy rate
 Syst Biol Reprod Med. 2017

45.  Hematopoietic and non-hematopoietic bone marrow-derived stem cells
(BMDSCs) are recruited to the endometrium in response to injury.
 Studies have supported the presence of progenitor cells in the
endometrium and these cells proved to have a high regenerative
capacity
 Endometrial stem cells are able to generate human endometrium after
transplantation in mice renal capsules.
Middle East Fertility Society Journal (2017) 22, 1–12

46.  STUDY DESIGN, SIZE, DURATION:
 OMECS were prepared from rat oral mucosal tissues. An
IUA model was made in rat uteri, and OMECS were
transplanted into the model. Uteri transplanted with
OMECS were compared with the non-transplanted control
uteri by histological analysis at 1, 2 and 8 days after
surgery (n = 3).
 WIDER IMPLICATIONS OFTHE FINDINGS:
 Transplantation of OMECS offers a reliable method not
only to protect the woman's fertility from intrauterine re-
adhesion after synechiotomy for IUA or uterine lumen
adhesion but also to prevent adhesion after any
intrauterine surgery in clinical cases.

47.  PARTICIPANTS/MATERIALS, SETTING, METHODS:
 After the initial hysteroscopic diagnosis, BMDSC mobilization was performed by
granulocyte-CSF injection, then CD133+ cells were isolated through peripheral
blood aphaeresis to obtain a mean of 124.39 million cells (range 42-236), which
were immediately delivered into the spiral arterioles by catheterization.
Subsequently, endometrial treatment after stem cell therapy was assessed in
terms of restoration of menses, endometrial thickness (by vaginal ultrasound),
adhesion score (by hysteroscopy), neoangiogenesis and ongoing pregnancy rate.
The study was conducted at Hospital Clínico Universitario ofValencia and IVI
Valencia (Spain)
.
 WIDER IMPLICATIONSOFTHE FINDINGS:
 This novel autologous cell therapy is a promising therapeutic option for patients
with these incurable pathologies and a wish to conceive.

48.  STUDY DESIGN, SIZE, DURATION:
 In this experimental, non-controlled and prospective 3-year clinical study
involving seven patients with AS, autologous menSCs were isolated and
cultured from menstrual blood of each patient within ~2 weeks and then
transplanted back into their uterus. Endometrial growth and pregnancy
were assessed after cell therapy.
 MAIN RESULTSANDTHE ROLE OF CHANCE:
 We successfully cultured menSCs from seven patients and transferred the
autologous cells back to their uterus. Our results showed that the ET was
significantly (P = 0.0002) increased to 7 mm in five women, which ensured
embryo implantation. Four patients underwent FET and two of them
conceived successfully. One patient had spontaneous pregnancy after
second menSCs transplantation.

49.  A few randomized controlled trials have shown that endometrial scratching
in the luteal phase of one cycle prior to IVF cycle increases the endometrial
thickness and pregnancy rate
 Tissue injury procedures such as endometrial biopsy induces stem cell
differentiation and increases endometrial receptivity.
 inflammatory reaction which favours
implantation. Dendritic cells, NK cells and
macrophages are employed to local injury
and increased amounts of inflammatory
mediators are secreted,
thus resulting in successful implantation
Journal of SouthAsian Federation of Obstetrics and Gynaecology, April-June 2018;10(2):81-83

50.  DISCUSSION:
The PIP trials are designed to address the gaps in the
utility of endometrial scratching as a treatment for
subfertility in three different populations. If the
beneficial effect of this intervention can be confirmed
in these settings, endometrial scratching will provide a
cost-effective method for helping women and couples
to conceive.

51.  METHOD:
Multicenter randomized controlled trial in Dutch academic and non-
academic hospitals. A total of 900 women will be included of whom half
will undergo an endometrial scratch in the luteal phase of the cycle prior
to controlled ovarian hyperstimulation using an endometrial biopsy
catheter.
 DISCUSSION:
Multiple studies have been performed to investigate the effect of
endometrial scratching on live birth rates in women undergoing IVF/ICSI
cycles. Due to heterogeneity in both the method and population being
scratched, it remains unclear which group of women will benefit from
the procedure.The SCRaTCH trial proposed here aims to investigate the
effect of endometrial scratching prior to controlled ovarian
hyperstimulation in a large group of women undergoing a second
IVF/ICSI cycle.

52.  STUDY DESIGN, SIZE, DURATION:
 This randomized controlled trial recruited 300 unselected subfertile women
scheduled for IVF/ICSI treatment between March 2011 and August 2013. Subjects
were randomized into endometrial aspiration (EA) (n = 150) and non-EA (n = 150)
groups according to a computer-generated randomization list.
WIDER IMPLICATIONSOFTHE FINDINGS
:
 Previous RCTs and meta-analyses have suggested improved pregnancy rates after
pretreatment endometrial injury in women with repeated implantation failure.A
recent RCT also showed increased pregnancy rates in unselected subfertile
women after endometrial injury, although that study was terminated early and
thus underpowered. Our study showed with adequate power that no significant
improvement in pregnancy rates was observed after endometrial injury in
unselected women undergoing IVF treatment.

53.  A new approach has been suggested for the treatment of thin
endometrium in the form of Intra uterine infusion of platelet-rich
plasma (PRP) by ChangY in 2015.
 This pilot study was carried out on 5 women with refractory thin
endometrium.They infused 0.5 ml of autologous PRP in uterine
cavity on day 9/10 and again on day 13/14 of cycle while the
patient was on estradiol valerate.There was satisfactory growth
of endometrium in all 5 with 4 live births and 1 missed abortion.
 Shahrzad Z et. al. in 2017 reported a similar pilot study on ten
patients; Five patients were pregnant with 4 live births
Int J Clin Exp Med. 2015; 8(1): 1286–1290
JBRA Assist Reprod 2017 Jan-Mar; 21(1): 54–56.

55.  CONCLUSIONS:
This is the first study evaluating the effect of
PRP on different human endometrial cells
involved in tissue regeneration.These data
provide an initial ex vivo proof of principle for
autologous PRP to promote endometrial
regeneration in clinical situations with
compromised endometrial growth and scarring.

56.  CONCLUSION:
Intrauterine administration of autologous
PRP stimulated and accelerated regeneration
of the endometrium and also decreased
fibrosis in a murine model of damaged
endometrium.

57. Treating patients with "thin" endometrium
- an ongoing challenge.
Lebovitz O1, Orvieto R. Gynecol Endocrinol.2014 jun
MATERIALS AND METHODS:
A literature review was conducted for all relevant articles
assessing the effect of various treatment modalities on "thin"
endometrium and the consequent reproductive outcome.
CONCLUSIONS:
"Thin" endometrium is known to adversely affect reproductive
performance.Treatment of "thin endometrium" remains a
challenge and future large researches are required to further
elucidate and optimal management of patients with "thin"
endometrium

58.  Thin endometrium affects the success outcomes
 Receptive endometrium with proper endometrial
development plays an important role in embryo
implantation
 Vaginal sildenafil during the stimulation cycle appears
to be a reasonable first-line treatment option
 Stem cell therapy appears to have a great role in the
refractory cases; however, more research regarding
safety, effectiveness, and cost is required.

59. Thank You..