The thin endometrium refers to the lining of the uterus, known as the endometrium, being insufficiently thick. This condition is typically characterized by a reduced thickness of the endometrial layer, which plays a crucial role in supporting the implantation and development of a fertilized egg during the menstrual cycle. A thin endometrium is commonly associated with hormonal imbalances, such as low estrogen levels, which are vital for the growth and maintenance of the endometrial tissue. Inadequate blood flow to the uterus, chronic inflammation, or certain medical conditions can also contribute to this condition. Women with a thin endometrium may experience difficulties in achieving and maintaining pregnancy, as the thin lining may not provide an optimal environment for the embryo to implant and thrive. Addressing the underlying causes of a thin endometrium often involves hormonal therapies to regulate estrogen levels, lifestyle modifications, and sometimes surgical interventions. Fertility treatments, such as in vitro fertilization (IVF), may be considered to overcome the challenges associated with a thin endometrium. In conclusion, a thin endometrium can pose challenges to fertility and reproductive health, requiring a comprehensive approach to address the underlying factors and improve the chances of successful conception.

1. Thin Endometrium- Where are we Today?
Dr Kaberi Banerjee
New Delhi

2. CONTENTS
1. DEFINITION
2. PREVALENCE
3. ASSESSMENT
4. CAUSES
5. TREATMENT

3. Endometrial thickness
• Maximal distance b/w echogenic interfaces of endometrium and
myometrium in plane of central longitudinal axis of the uterus
• Assess endometrial receptivity

4. Definition
• An endometrium thickness that can’t reach the threshold for
embryo implantation.
No agreement
• ≤6 mm
[Gonen et al, 1990; Shapiro et al, 1993; Coulam et al, 1994]
• <7 mm
[Rinaldi et al, 1996;Kovacs et al 2003; Zhang et al, 2005;
Richter et
al, 2007; El-Toukhy et al, 2008; Kumbak et al, 2009}
• ≤8 mm
[Gingold et al, 2015]

5. • Clinical Pregnancy and Live birth rates decrease for each mm of
endometrial thickness
• <8mm in fresh IVF cycles and < 7mm in FET cycles

6. • Live birth rate 15-20% in Fresh IVF where ET was
between 5-6mm
• And FET where ET was between 4-6mm

9. PREVALENCE
40% - Ovarian
Stimulation
Cycles
2-10% - IVF
cycles

10. ASSESSMENT
• Ultrasound
• Most often used
modality
Thickness and Pattern
Volume
Doppler of uterine
and sub-endometrial
blood flow.

11. Significance of Endometrial
pattern
• Grade A – Triple Layer
• Grade B – Intermediate echogenecity as
myometrium
• Grade C – Homogenous hyperechoic
• EP is a better indicator of the probability of
pregnancy than ET.
• Trilaminar pattern with ET ≥6 mm suggests
that implantation may not be compromised

12. Endometrial Volume
• Uterine cavity volume by 3D or
4D sonography, a volume of 3 –
5 cc in midcycle phase is
optimum for good receptivity.
• Role for predicting IVF outcome:
controversial.

13. Doppler
• Not universal predictors of
pregnancy in IVF Cycles
Mercé et al., 2008; Ng et al, 2009; Zhang et al, 2016

14. CAUSES -I. Inflammatory causes
– Acute or chronic infection:
destruction of the basal layer of
the endometrium.

15. II. Iatrogenic
Surgical
1. Repeated or vigorous curettage
2. Aggressive myomectomy
3. Partial ablation
4. Radiotherapy
Medical
1. Clomiphene Citrate
2. Prolonged progesterone therapy:
3. Combine Oral Contraceptive Pill

16. III. Congenital Müllerian anomalies and POF
• The association
between Müllerian
anomalies and POF
with refractory
endometrium is
documented in the
scientific literature.

17. IV.
Idiopathic:
• Thin endometrium not secondary to
a disease process.
• It can result from individual uterine
architecture intrinsic properties of
endometrium that affect its growth.
Strohmer et al, 1994 Scioscia et al,
2009

19. TREATMENT
I. Hysteroscopic adhesiolysis
II. Treating Infections
III. Hormonal manipulation
Estrogen: PO, transdermal, IM and vaginal.
HCG injection in the proliferative phase
Midluteal GnRHa
III. Improving endometrial perfusion
LDA
Pentoxifylline and vitamin E.
Sildenafil.
L-arginin
Nitroglycerin
IV. New modalities
Granulocyte colony-stimulating factor
Autologous platelet-rich plasma
Endometrial stem cells from bone marrow

20. Hysteroscopic Adhesiolysis
• Primary Prevention
• Gentle Curettage
• Myomectomy
• Skilled Hands
• Use less current
• Use Inert Material
• Estrogen
(AAGL 2017)

21. Treating Endometritis
Symptoms and Signs
EB- Plasma Cells
Hysteroscopic- Hypermemia, Micropolyps
Treatment- Doxicycline 100mg twice daily 14 days both partners
Intrauterine antibiotics

22. Female Genital
Tuberculosis

23. Infertility
• Primary and secondary infertility
- FGTB
• Fallopian tubes – 90 % (Tubal
block)
• Uterus – 70 % (Affects
endometrial receptivity)
• Ovaries – 25 % (Chronic
anovulation)

25. Investigations
Blood test: CBC, ESR X-ray chest (PA view) Mantoux/(Tuberculin) test
and interferon gamma
release assay (IGRA)43
Microbiology - Endometrial
biopsy, curettage or aspirate
(TB PCR/Gene Xpert/AFB
culture)

26. TB-Imaging
methods
• Ultrasonograp
hy (USG) - TO
masses with
calcification
and fluid in
POD
• HSG
• (CAT) scan
• MRI
• PET scan

27. Hysteroscopic
Findings
• Pale looking cavity
• Tubercles
• Caseous nodules
• Synechiae
• Asherman’s syndrome

28. Laparoscopic
Findings
• Subacute
• Congestion
• Oedima
• Miliary tubercles
• White or yellow
patches in pelvis
• Chronic
• Small swollen tubes
• Tubal block
• Beaded tubes
• Hydro/Pyosalpinx
• Caseous nodules
• Perihepatic Synechiae

29. Management of Genital Tubercolosis
Composite Reference
Standard (CRS)
AFB positive HPE-Granuloma
Gene Xpert (Cartridge
based nucleic acid
amplification
test)positive
Laparoscopic and
Hysteroscopic
definitive finding
PCR positive with
infertility and any
probable finding

30. Treatment

31. Treatment
• First line drugs (rifampicin,
isoniazid, pyrazinamide,
ethambutol daily for 60 days
followed by rifampicin,
isoniazid, ethambutol daily
for 120 days)
– Second line drugs for 18-
24 months for drug-
resistant (DR) cases

32. Treatment
DOTS follow up
(Directly observed
treatment short
course strategy)
http//nikshay.in

34. Estrogen and Types
• Estrogen helps endometrial proliferation
facilitates embryo implantation
• Oral
• Vaginal
• Transdermal
• First pass effect is bypassed
• High local concentrations
• Equal or better
• No Consensus

35. Oral Vs Transdermal-FET Cycle
• Undergoes first pass metabolism.
• Metabolized into Folliculin in liver
and small intestine.
• Folliculin activate the Oncogenes in
breast and endometrium.
• Increased risk of venous
thromboembolism.
• Increased risk of breast cancer and
CVD related hospitalization.
• Bio-availability is less than
transdermal form.
• High dose of Oral Tab cause-
Gastritis and Nausea
• Avoid first pass metabolism.
• Bioactive form.
• Avoid the side effect arising from
first pass metabolism.
• Maintain stable serum estradiol
level.
• Reduced risk of venous
thromboembolism.
• Bio availability of transdermal
Estradiol is 2 times higher than
the oral form.
• Due to dermal application avoid
such side effect.
Oral Estradiol Estogel

36. Sr Estradiol Hemihydrate Estradiol Valerate
1 Most physiological form of estrogen available;
Chemically and biologically identical to the
endogenous human estradiol
Slight modification of the natural molecule
(esterified form)
2 17ß-estradiol metabolizes to estrone, estriol and
estrone sulphate
Metabolizes in the liver→to 17ß-estradiol and
valerian acid → to estrone, estriol and estrone
sulfate
3 Minimal load on the liver More load on the liver than when using 17ß-
estradiol
4 Unconjugated, hence rapidly available after
ingestion
Compared with estradiol hemihydrate,
slightly lower estrone levels are found, as
valerate slows down the intestinal
metabolization of estradiol
5 Following oral administration and absorption,
17-β estradiol circulates in the plasma as “free”
estradiol. Due to the large surface of the
microcrystals, a sufficient quantity of estradiol is
absorbed rapidly and thus escapes metabolization
Oral therapy is subjected to an extensive first
pass metabolism
6 Estradiol hemihydrate diffuses through the cell
membrane and binds to and subsequently
activates the nuclear estrogen receptor
The affinity of estradiol valerate for the
estrogen receptor is lower than that of
estradiol
References:

37. Dose and
Duration
of
Estrogen
Dose- can go up to
12 mg daily
Duration-usually
2-3 weeks
Transdermal-one
actuation=0.75mg

38. HCG
• HCG is produced by endometrial epithelial cells in the secretory phase, where
HCG receptor have been identified
• HCG would play a local paracrine role in differentiation and endometrial
receptivity by regulating different cytokines and growth factors.
Dose:
150 iu SC, daily starting from day 8 of the cycle
For 7 days or until ET 7mm
endometrial thickness
clinical outcome.
Papanikolaou et al. ,2013; Davar et al, 2016

39. HCG

40. GnRH-a • Significantly improves ET and Pregnancy Rates
• No Further Validation
Luteal phase support with GnRH -a improves implantation and
pregnancy rates in IVF cycles with endometrium of 7 mm
on day of egg retrieval
H. QUBLAH1
, Z. AM ARIN2
, M . AL-QUDA, F. DIAB1
, M . NAWASREH1
, S. M ALKAWI1
, &
M . BALAWNEH1
1
Infertility & IVF Center, Prince Rashed Hospital, Irbid, Jordan, and 2
Infertility & IVF Center, Jordan University of
Science and Technology, Irbid, Jordan
Background
Objective: The objective of this study was to examine the use of gonadotrophin-releasing hormone agonist (GnRH-a) for
luteal phase in a group of patients with thin endometrium ( 7 mm) after IVF treatment.
Methods: One-hundred-and-twenty women were eligible for this study. Patients were randomly allocated into two groups:
group A (n ¼60) received triptorelin 0.1 mg on the day of ovum pickup (OPU), on the day of embryo transfer (ET) and
three days thereafter, and group B (n ¼60) received placebo. The primary outcomes were implantation and pregnancy rates.
Human Fertility, M arch 2008; 11(1): 43 –47

41. Improving
Endometrial
Perfusion

42. Low Dose Aspirin
• Reduces inflammation by
inhibiting cyclooxygenase
and prostaglandin
biosynthesis
• Improves uterine
endometrial blood flow
• Reduces subendometrial
contractility

43. Low Dose
Aspirin
Weckstein et al.(1997) :
higher implantation and CPR
unrelated to any improvement in
ET, but
improved endometrial blood flow
 Hsieh et al (2000). on women who
underwent IUI with a thin
endometrium:
higher PR (18.4% vs 9%)
improved EP, not ET or uterine
vascular flow

44. Vit E and
Pentoxifylline
• Pentoxifylline - Increases
intracellular cAMP and has
vasodilatory effect.
• Used in the symptomatic
treatment of vascular
pathologies
• Vit E – Antioxidant and
Vasodilator

45. Vit E and Pentoxifylline
§Pentoxifylline: 800 mg
§vit E: 1000 IU
§daily for 6-9 months:
(Kitaya et al.,2014)
• §Treatment should be suspended prior to ET
Widely used in Patients who received RT

46. Sildenafil
• Enhances the
vasodilator effect of
nitric oxide by
reducing cGMP
degradation.
• It exerts its action at
the endothelial
smooth muscle

47. Sildenafil
 Sher and Fisch, 2000
 Dose:
25 mg/6 h in vaginal supp
in the follicular phase
stopped prior to HCG administration or ET.
Increase
uterine artery blood flow
EnT
 Zinger et al.2006
 Asherman syndrome.
2 successful cases

48. Sildenafil
Evidence for the clinical
benefit of sildenafil in
women with a recurrent
thin endometrium: weak
Prospective, RCT
No benefit of sildenafil on
EnT.
(Check et al.,2004)

49. L- Arginine
and
Nitroglycerine
L - Arginine
Regulates
vasodilation and
inflammatory
response
6 gm/day
NO - vasodilating
agents
No strong evidence

50. New Modalities

51. Granulocyte colony‐stimulating factor (G‐CSF)
• Hematopoietic‐specific
cytokine
• MOA
• Increases endometrial
stromal cell
decidualization mediated
through cAMP by
apocrine and paracrine
action
• Inducing proliferation and
differentiation of
endometrium

52. G‐CSF
• Route of administration
• Subcutaneous
• Intrauterine
• Dose – 300 mcg/ml per
injection
• Timing
• Given after 12 to 13
days of estradiol, HCG
day, OPU day
• Effects come in 48 to 72 hrs

56. Role of subcutaneous G CSF
infusion in thin endometrium
Dr Kaberi Banerjee
Dr Bhavana Singla
Dr Priyanka Verma
Advance Fertility and Gynae Centre,
6, Ring Road, Lajpat Nagar 4, New Delhi 110024

57. • To assess the role of
subcutaneous
granulocyte colony-
stimulating factor (G-
CSF) in thin
endometrium cases.

58. Materials and Methods
• Design: Retrospective analysis
• Subjects: 107 infertile females with thin
endometrium (< 7 mm) on Day 12 or 13
undergoing ART cycles
• Age group: 23 to 40 years
• Duration: 6 months
• Groups: Group 1 (with G CSF) & Group 2
(without G CSF)

59. Materials and Methods
• Group 1
– 48 females,
– S/C infusion of G CSF (300 mcg/ml) was given at
10th or 12th day + sildenafil 50 mg + aspirin 75 mg
– Repeated in 72 hours - if lining was not > 7 mm
• Group 2
– 69 females
– Only sildenafil + aspirin
• Assessment of efficacy of G CSF - By
pregnancy outcome

60. Criteria of Embryo Transfer
• Embryo transfer performed when
– Thickness >7.5 mm
– Subjective improvement of echotexture in 2D USG
• Cancellation of ET
– In group 1 – 4 cases
– In group 2 – 15 cases

61. Results
• No difference in two groups regarding
demographic variables, egg reserve, sperm
parameters, number of embryos transferred
and embryo quality
• Pregnancy rate
– Group 1 - 59% (26 out of 44 cases)
– Group 2 - 27% (12 out of 44 cases)
• p value < 0.0001 (Significant)

62. Pregnancy Rates
59%
27%
0
5
10
15
20
25
30
Group 1 Group 2
p value < 0.0001

63. Conclusion
• First study in India - showed subcutaneous
role of G CSF in thin endometrium
• Huge promising role in improving fertility outcome in
widely prevalent cases of endometritis and thin
endometrium

64. Autologous Platelet-rich Plasma
Collected from peripheral vein
Through activating platelets by
clotting, releases
Cytokines and growth factors:
VEGF
transforming growth factor
platelet-derived growth factor
and
epidermal growth factor.

65. • Estradiol valerate was given on day 3 of
menstrual cycle.
• On the 10th day of HRT cycle, 15 ml of venous
blood was drawn from the syringe pre-filled with
5 ml of anticoagulant solution (ACD-A), and
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 re-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.
• It was infused into the uterus cavity
immediately with IUI canula
• Endometrial thickness was re-assessed 72 h
later.
• If the endometrial thickness was not
satisfied,infusion of PRP was performed 1-2
times..

66. Mobilizing Endometrial Stem cells from Bone
marrow
These cells incorporate into the
endometrium in small numbers and
transdifferentiate into
• endometrial epithelial stromal
and endothelial cells

67. Hysteroscopic Instillation of
PRP

68. Journal of Human Reproductive Sciences
Autologous stem cell transplantation in refractory Asherman's syndrome: A novel
cell based therapy
Neeta Singh, Sujata Mohanty, and Sona Dharmendra
• The isolation of mononuclear cells (MNCs)
was done by Ficoll density separation
method.
• BM was diluted in 1:3 ratio with ×1
phosphate buffered saline (PBS) and
layered over lymphocyte separation
medium and centrifuged at a speed of 800
G for 25 min.[
• MNCs (buffy coat) was aspirated with 10
ml disposable pipette and washed thrice
in heparinized normal saline (NS)/PBS to
remove the traces of Ficoll.[
• All the procedures were performed in the
stem cell laboratory. Finally, MNCs were
suspended in 3 ml heparinized NS.
• The harvested MNC were evaluated for:
• Viability, Cell morphology and CD34
counts

69. • Same day the patient was taken up for stem cell implantation.
• Stem cell implantation
• The procedure was conducted under intravenous (IV) sedation and
antibiotic cover (single dose of 1 g cefazolin IV).
• Patient was laid in lithotomy position. A transvaginal probe was covered
with sterile disposable probe cover and guide attached to it. After locating
the sub-endometrial zone on ultrasound (Wipro GE
• Voluson) ovum pick up needle (Cook No. 17) was introduced vaginally via
the lateral fornix and stem cells were implanted in the sub-endometrial
zone transmyometrial. A volume of 3 ml of MNC were delivered at 2-3 sites
(fundus, anterior and posterior part) of the myometrium.
• 5/6 women resumed menstruation

70. Endometrial
Receptivity Array (ERA)
• Genetic test to diagnose state of
endometrial receptivity in window of
implantation
• Endometrial biopsy –
• Natural cycle at day 21 i.e 7 days after
LH surge LH+7 or 6 days after the
follicle rupture, when monitored by
ultrasound)
• Hormone replacement therapy cycle
after 5 full days of progesterone
impregnation in HRT cycles

71. Interpretation of
Result
• (R) Receptive :
• Advised to
proceed with ET
in same
conditions, type
of cycle and day
when EB has been
done
• (NR) Non Receptive
:
• New EB to be
taken to validate
implantation
window
displacement and
guide ET

74. www.advancefertility.in
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75. www.advancefertility.in
Management of Thin Endometrium at AFGC
Rule of any cause and treat endometritis
(monitor in a non medicated cycle, Hysteroscopy)
Build Endometrium
Plain Estradiol valerate, max 12 mg, upto 3 weeks
Can change prep if one doesn’t work
Can change protocol like Letrozol, low dose HMG
Downreg cycle preferred in adenomyosis and endometriosis

76. Endometrial Preparation for FET
Natural Cycle (NC)
Hormone Replacement
Cycle
(HRT)
Stimulated Cycle
HRT without DR
Pure natural cycle
Modified Natural
Cycle(MNC) Down-regulated HRT
(DR-HRT)

77. www.advancefertility.in
Use of Adjuvants
Usually
Sildenafil
G-CSF
Aspirin
Lately
GnRHa
Low dose HCG
PRP

78. www.advancefertility.in
Points To Remember
• Ensure Downregulation
• Monitor growing follicle
• Progesterone from day of ovulation
• No transfer if Spotting or Fluid
• Good Embryos
• Good Transfer Technique
• Persistently thin , do not try more than 2-3 attempts
• Stop treatment/ Adoption/ Surrogacy

79. Specific Questions
• Thin endometrium with CC?
• Thin endometrium in IUI?
• Thin endometrium in Fresh cycles?
• Thin endometrium in FET?

80. e et al., 2013; Hafany et al.,
conducted in Saudi Arabia in
who underwent hysterectomy
tpartum haemorrhaging. The
with benign ovarian cysts. Two
after transplantation, but the
ed after 99 days owing to pro-
ombosis (Fageeh et al., 2002).
probably caused by not enough
edge of the procedure at that
ferent animal models, includ-
enstruation recovery, and even
ery published for the first time
cynomolgus monkey in 2012
h (Ozcan et al., 2013) and a
14) group recently performed
ations in young women. The
st 2011 in Turkey on a woman
eived a uterus from a brain-
woman due to a traffic acci-
other nine cases were carried
women with MRKH syndrome
hysterectomy because of cer-
uterus from four premeno-
l women, of whom five were
Table 2 Summary of described efficacy of the different thera-
peutic options for refractory endometrium No evidence of
benefit Unclear effect Benefitial intervention.
Therapeutic option
Efficacy
Endocrine strategies
high doses of estradiol
long courses of estradiol
vaginal estradiol
systemic HCG
intrauterine PRP
intrauterine G-CSF
GnRH analogues
AAS, vitamins & supplements
aspirin
nitroglicerin patches
vitamin E
L-arginine
pentoxifiline
sildenafil
Surgical strategies
hysteroscopy
stem cells
uterine transplantation
JA Garcia-Velasco et al.

82. • Not reflective of our
population
• No mention of
endometritis
• Aspirin study
• Limited studies of other
medications
• Gross Generalization
• No study of other
parameters of endometrial
assessment
• No RCTs does not mean no
benefit

83. Conclusion
Thin Endometrium is a strong marker of poor
endometrial receptivity, but not always
Rule out treatable causes
Stepwise approach- Estrogens, LDA, Sildenafil and G-
CSF
Change Protocol
What works for one , may not work for the other
What works in one cycle, may not work in the next
cycle
Explore Vit E, Pentoxiphyline, HCG, GnRH- a and PRP
Stem Cell only in Clinical Trial Setting
Know where to draw the line.

84. Indian Setting
• Different problems
• Huge data base
• Urgently need good quality
studies