THIN

ENDOMETRIUM
DR. ASTHA GUPTA
SENIOR IVF AND INFERTILITY CONSULTANT
MILANN FERTILITY, DELHI
PREGNANCY LOSS ICEBERG

Human Reproduction Update, 2002

 IVF FAILURE

Success of IVF cycle is mainly dependent on

 

 Age

 Quality of the Embryo

 Endometrial receptivity
REASON FOR FAILURE-
what can be changed??
ESTABLISHING
IDEAL SOIL-SEED
RELATIONSHIP!!!
 Successful human implantation is an interaction-
(1) Embryo development 
(2) endometrial differentiation.
 A synchrony produces a transient period of
implantation- NIDATION/IMPLANTATION WINDOW.
 Healthy embryo needs Receptive Endometrium for
successful implantation.
RECEPTIVE
ENDOMETRIUM ON USG
 Endometrial thickness

 Endometrial pattern

 Endometrial and
subendometrial blood flow

 Endometrial volume
 ENDOMETRIAL
THICKNESS
 Indirect indicator for
endometrial receptivity.
 Measured on TVS as the
“maximal distance
between the echogenic
interfaces of the
myometrium and
endometrium in the
plane through the central
longitudinal axis of the
uterine body”.
 THIN ENDOMETRIUM

 An endometrial thickness that can’t reach threshold for

embryo implantation.
El-Toukhy T,  et al. Fertil Steril 2008

 Mostly defined as an endometrial thickness of<7mm on

ultrasound- the sensitivity and specificity 100% 
Moustafa Abdel Kader, The Egyptian Journal of Radiology and Nuclear
Medicine, 2015

 Cut off value of 6mm and 8mm has also been used.
Dain et al 2013
THIN ENDOMETRIUM-
PREVALENCE??

More
 often in older women –decreased
vascularity. 

<40
 years - Incidence of 5%
> 40 years- 25% in natural cycles.


 Kasius et
 al. 2014  reported an incidence of 2.4%
in their meta-analysis that included 1170 patients
undergoing IVF.
 SURROGAC
Y

RESULTS

THIN
ENDOMETRIUM

REPEATED UNPLANNED
CYCLE CRYO
CANCELLATION PRSERVATION
OF EMBYROS
Thin endometrium-
importance??

 ET gives the probability of pregnancy in ART

cycles

 Thin endometrium - associated with poor success

rates after IVF irrespective of the causative factor

 
CAUSES OF THIN ENDOMETRIUM

 Low level of estrogen

 Endometrial resistance to estrogen

 Reduced endometrial blood flow

 Permanent damage to basalis layer

ETIOLOGY: Inflammatory

 Acute or chronic infection

 Endometritis- vigorous curettage

 In India, genital Koch's is the most common cause of

thin endometrium.

 Since healing takes place by fibrosis, it leads to the

destruction of the endometrium and shrinkage of the
uterine cavity.
 ETIOLOGY : Iatrogenic

 Surgical –
 repeated or vigorous curettage
 Hysteroscopic myomectomy, polypectomy, or
laparoscopic myomectomy

 Medical – indiscriminate use of drugs such as

clomiphene citrate, prolong use of COC.
.  

ETIOLOGY

 Secondary to a disease process e.g. Fibroids,

adenomyosis, mullerian anomalies.

 Intrinsic properties of endometrium that affect its

growth.
 PATHOPHYSIOLOGY

Adequate endometrial development--dependent on adequate blood

supply.
 Vascular epithelial growth factor (VEGF) -  Plays A
Critical Role In Angiogenesis

 Increased impedance across the radial uterine arteries-

decrease in VEGF expression and subsequent poor
vascular development, resulting in thin endometrium .
 PATHOPHYSIOLOGY

 Basal layer, homes the

larger-caliber oxygen-
rich spiral arteries.
 Proximity to the ROS-rich
basal layer is detrimental
for embryo development
and implantation
Treatment modalities
 Hormonal replacement therapy
 Vaginal sindenafil
 G- CSF
 Pentoxifylline and tocopherol
 Low dose aspirin
 PRP
 Stem cell therapy
 Acupuncture
 neuromuscular electrical stimulation (NMES)
 Others like nitroglycerine, arginine
 HORMONE REPLACEMENT
THERAPY
1.Estrogen
 Principle:
 water imbibition and cellular proliferation

 Causing spiral artery contraction and

decreasing oxygen tension in the
functional layer, that simplifies embryo
implantation
M.A. Bedaiwy et al. Reprod.Bio Endocrinol.,2011.
 OESTROGEN

 Timing-
 Administration at start of cycle
 Earliest possible
 Before fourth day
 Duration of oestrogen exposure - 6-38 days( atleast 12
-14 days) before progesterone supplementation
 Shorter oestrogen supplementation(<6 days) - higher
abortion rate and breakthrough bleeding occurs after
>40 days of supplementation.
20
 ROUTES

 ORAL- Estradiol valerate , Constant or increasing dose

 Undergoes first pass metabolism in liver to estriol

 Circulatory estrogen decreases by 30%
 Estradiol valerate : estrone ratio- .2

 TRANSDERMAL-
 Escape first pass metabolism
 More physiological estradiol: estrone ratio-1
 Avoid systemic side effects
 Fluctuation in estrogen concenteration
21
 ESTROGEN
VAGINAL

Advantages-
 Comparable implantation and clinical pregnancy rate per
transfer cycle.
 Skips first pass metabolism and hence higher bioavailibility:
used in patients with inadequate endometrium
Disadvantages-
 Damages effect of vaginal progesterone used for luteal
Support.
 Local irritation
 ESTROGEN

 Dose, route and regimen differ widely – NO

CONSENSUS.
HRT: GNRH AGONIST
IN LUTEAL PHASE

 0.1 mg of Triptorelin given on days of egg

retrieval, embryo transfer, and 3 days
after embryo transfer- endometrial
thickness and pregnancy rates –
significantly higher in GnRH a group.

 Level of evidence - WEAK

 HRT: HUMAN CHORIONIC
GONADOTROPIN

 Local paracrine role in the endometrium differentiation and

endometrial receptivity by regulating different cytokines and
growth factors
 Significantly improved results ET, Endometrial receptivity and
clinical pregnancy rates both during fresh and frozen cycles .
Papanikolaou et al. 2013,
Davar et al 2016

 No RCT or metanalysis
 HRT: TAMOXIFEN

SERM - estrogen agonist effect at the level of the

endometrium.
 A recent prospective observational study included 226
participants with a thin endometrium in FET cycles-
Tamoxifen cycles showed a significantly increased ET

Hanni k et al.2017
 HRT: TAMOXIFEN

Mechanism of action:
increase in endometrial
thickness

modulating estrogen
non- estrogen pathway.
biosynthesis and metabolism

up-regulates the Paracrine factors f

expression of Ki67 which stromal cells
is a marker of
Activate ER, modulate signal
proliferation
transduction

Lin BC, Suzawa M, Blind RD, Tobias SC, Bulun SE, et

al. (2009) .
 HRT: TAMOXIFEN

Larger cohort studies aiming to

elucidate the effect of tamoxifen and
the efficacy of tamoxifen for different
causes of thin endometrium remains
elusive.
TOCOPHEROL (VITAMIN E)
AND PENTOXYPHYLLINE

 Pentoxifylline (PTX) as a derivative of methylxanthine -

induce vasodilatation
 Vit E-Improves growth of glandular epithelium- improves
vascularity and increases VGEF.
 Improvement in endometrial thickness and pregnancy
rate of 40% in treated patient
S. Acharya et al, Hum. Fertil, 2009
 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). 
Takasaki,et al. (2010)
TOCOPHEROL (VITAMIN E) AND
PENTOXYPHYLLINE

 Has been used to treat radiation induced thin endometrium.

 Long courses of PTX and tocopherol were used in oocyte-donor recipient

patients, POI ,unexplained infertility, and patients who received
radiotherapy. N. Lédée-Bataille,et al. (2002)

H. Letur-Konirschet al.  (2003)

 Trials noted a significant improvement in EMT, there was no evidence of a

significant improvement in pregnancy rates.

 Long duration of treatment…. Didn’t gained much popularity

 LOW DOSE ASPIRIN
 Role has been controversial in IVF outcomes
 Reduces uterine vascular resistance and
improved uterine flow rate.
 evidence regarding endometrial thickness are
not significant 

Management of thin endometrium in

assisted reproduction: a clinical practice
guideline from the Canadian Fertility and
Andrology Society 2019
 LOW DOSE ASPIRIN

 A systematic review and meta-analysis by Wang, MS

liping et al,2017 3 studies (311 participants) that
reported on endometrial thickness showed No
significant change in the rate of endometrial
thickness between aspirin and placebo treatment
groups.
ROLE OF L ARGININE AND
SILDENAFIL
L arginine(a
substrate of NO)

NO

activating cyclic
guanosine
monophosphate
(cGMP)

relaxation of
vascular smooth
muscle
33
ROLE OF L ARGININE AND
SILDENAFIL
Sildenafil
citrate(type 5
specific
phosphodiesteras
e inhibitor)

prevents the
breakdown of
cGMP

potentiates the
effect of NO on
vascular smooth
muscle

34
 VAGINAL SILDENAFIL

 l arginine and sildenafil citrate significantly improved

uterine A RI and endometrial thickness in the patients
with a thin endometrium.
Tasaki et al, 2010, fert stert
 Sildenafil vs control

 Significantly higher endometrial thickness

 Significantly higher triple line pattern
 Higher chemical pregnancy and implantation rate (non significant)

Firouzabadi et al, 2013, Iran J Reprod Med

VAGINAL SILDENAFIL

Management of thin endometrium in assisted

reproduction: a clinical practice guideline
from the Canadian Fertility and Andrology
Society 2019
PLATELET RICH PLASMA

 New approach

 Plasma prepared from fresh whole blood rich in platelets

 PLATELET RICH PLASMA
 Activating platelets in PRP- cytokines and growth
factors (GFs) become bioactive and are secreted
within 10 min
 MOA: contains several growth factors that
stimulate proliferation and growth (VEGF, EGF,
PDF, TGF)
 Process of PRP therapy
15 ml of venous blood was drawn from the syringe pre-
filled with 5 ml of anticoagulant solution (ACD-A)

centrifuged immediately at 200 g for 10 min

The blood was divided into three layers: red blood cells
at the bottom, cellular plasma in the supernatant and a
buffy coat layer between them

The plasma layer and Buffy coat were collected to

another tube and centrifuged at 500 g for 10 min

The resulting pellet of platelets was mixed with 1 ml of

supernatant, and then 0.5-1 ml of PRP was obtained.
ROLE OF PRP IN THIN
ENDOMETRIUM….
 1st documented case series by Chang et al in 2015 in
china- Successful endometrial expansion and
pregnancy were observed in all the patients
 A review article by Garcia-Velasco et al. published in
2016 - use of autologous PRP as a potential method of
improving ET in women with refractory endometrium.
 The mean pre-PRP ET was 5 mm and the post-PRP ET
was 7.22 mm (P < 0.00001 at 95% confidence interval)
Sunita R tendulwadkar. 2017
ROLE OF PRP IN THIN
ENDOMETRIUM….
 Although these preliminary studies are promising
for a population which has a poor prognosis and
few options for treatment, further research and
controlled studies are required

Management of thin endometrium in

assisted reproduction: a clinical practice
guideline from the Canadian Fertility and
Andrology Society 2019
GRANULOCYTE COLONY
STIMULATING FACTOR
 Glycoprotein produced by various cells and
tissue of the body(vascular endothelium , marcophages,
monocytes, fibroblasts)

 The human endometrium expresses G-CSF

mRNA and its receptor throughout the
menstrual cycle.

 Play a physiological role in endometrial

development.
GRANULOCYTE COLONY STIMULATING
FACTOR
MECHANISM OF ACTION-
 Alters expression of endometrial genes important
for implantation.
 Endometrial vascular remodelling
 Local immune modulation
 Stimulate and mobilize bone marrow stem cells
promoting endometrial development.
 GRANULOCYTE COLONY
STIMULATING FACTOR
 Absorption: absorbs rapidly through intrauterine/ subcutaneous
pathway

 Reaches peak within 4-5 hours

 Rapidly distributed within bone marrow, liver, kidney and adrenals

 T ½-- 3.5 hours ( with both routes)

 Comes in recombinant form (pfs containing 300micrograms)

G CSF

 Gleicher et al., 2011, was the first to report that IU G-CSF

instillation improves ET.

 Subsequently, many studies have been published some

reporting improvement while others do not show any
difference.
AUTHOR YEAR STUDY GROUP ENDOMETRIA IMPLANTATI CPR
L THICKNESS ON RATE

Xu et al 2015 30 patients with ET increased ↑ ↑

EMT < 7 mm during significantly (significantly ( significantly
FET cycles to ) )
intrauterine G-CSF

Barad et 2014 141 women - Significant NS NS

al. 2014 undergoing IVF. increase
73 patients to
receive G-CSF
(Filgrastim, Amgen,
300 μg/1.0 mL) and
68 -placebo
(saline).

J. Zhao 2016 Six studies with 607 NS NS statistically

in 2016 participants were significant
analyzed increase
 G CSF

 No consensus for dose, route of

administration when using G CSF for thin
endometrium

Management of thin endometrium in assisted

reproduction: a clinical practice guideline from
the Canadian Fertility and Andrology Society
2019
STEM CELL THERAPY

 New promising approach

 Endometrial growth is dependent on angiogenesis

 Recruitment of local endothelial cells
 Endothelial progenitor cells circulating in peripheral
blood after released from bone marrow.
 Procedure- Stem Cell Therapy

45 ml
aspirated
Endometrial
angiogenic
Bone stem cells are
marrow separated
aspiration in
10 ml
syringe
prewash
with heparin
Supplied in 0.7 ml
buffer saline with
2% autologous
stem cells
EVIDENCE-- STEM CELL
THERAPY
 Promising results

 Those with persistent thin endometrium refractory to

other treatment
 Asherman syndrome
 Treated tuberculosis patients with thin endometrium

C.B. Nagori, S.Y. Panchal et al J. Hum. Reprod. Sci. (2011)

N. Singh et al 2014
X. Santamaria et al. Hum. Reprod. (2016)
 STEM CELL THERAPY

Only case reports and case series are in

the literature, with no controlled studies
reported. Further research to evaluate the
potential risks and benefits of this therapy
is required

Management of thin endometrium in

assisted reproduction: a clinical practice
guideline from the Canadian Fertility and
Andrology Society 2019
 NMES
 Bodombossou-Djobo et al. evaluated 41 subjects with
an ET ⩽ 7 mm who failed to conceive in two prior ART
cycles .

 ET significantly increased in the treatment group

compared to the control group ( P = 0.002) but without
a significant difference in the clinical pregnancy rates
between the two groups.
No role documented for…

 Steroids

 I/V immunoglobulins

 Intralipid ???

 acupuncture
TAKE HOME MESSAGE
 A receptiveendometrium is an essential part of embryo implantation process, and
inadequate endometrial growth is associated with lower possibility of pregnancy.

Many treatment modalities have been applied to improve endometrial receptivity, but
their efficacy remains controversial.

 Largerandomized trials should be conducted to evaluate method, dosage, timing of

administration and outcomes of these treatment approaches.

No consensus on use of LDA, Arginine, nitric oxide, pentoxiphylline and

tocopherol

Sildenafil and HRT most commonly used based on clinical experience.

G CSF and PRP-- clinical use increasing

To conclude
“MORE
WORK NEEDS
TO BE
DONE”
THANKYOU