IUI / IVF failure causes lot of distress to both patient and the doctor They feel they are useless Lots of questions No clear answers

1. Thin Endometrium & Infertility
Dr. Sharda Jain
Dr. Jyoti Agarwal

2. Doctor , why did my IUI /IVF cycle fail ??
• IUI / IVF failure
causes lot of distress
to both patient and
the doctor
• They feel they are
useless
• Lots of questions
• No clear answers

3. Surprised to learn ….
Monthly fecundity rate in
normal couple is 20 – 25 %
60 % of the ivf cycles do
not end in pregnancy

4. Patient need to have realistic expectation
What went wrong
???

5. What can be changed ???
• Egg
• Sperm
Uterus
•Clinic
Treatment of
infertility can be a
roller coaster ride

6. Hard Facts
• Healthy seed just is not
enough to get a healthy
plant unless it is grown on
fertile soil
• Similarly healthy embryo
needs receptive
endometrium for
successful implantation.

7. USP of endometrium
• Human endometrium is
highly regenerative
tissue.
• It’s regenerative potential
is comparable to that of
bone marrow epidermis
& the intestine.

8. Then why fertility and
implantation in human beings
is naturally low ??

9. Endometrial function
And
endometrial receptivity
are major limiting factors in the establishment of pregnancy

10. Today we have improved all aspects of
IVF
but still ….
Average pregnancy rate of 40 – 50 %
cannot be further increased

11. The bottle neck is the
process of implantation

12. • Implantation is the most vital part of
reproduction
• Unfortunately is the least understood part
In fact it can be regarded as the
“Rate – Limiting step” in reproduction

13. Preparation of endometrium is directed
towards the window of implantation

14. Window of implantation starts 6/7 days after
ovulation when the secretary activity of the
gland is at its maximum and at this time
endometrium is best prepared for
implantation of blastocyst ie day 20 /21
It lasts for 4 – 5 days

15. Endometrial receptivity during the window of
implantation depends on
• Endometrial thickness
• Endometrial pattern
• Endometrial and
• Sub endometrial blood flow
Endometrium is usually hostile for an embyro
except during WOI

16. Clinical Importance of Endometrium
Successful implantation depends on a close dialog
between the blastocyst and the endometrium
Thin endometrium may be because of:
1. Endometrial resistance to cirulating oestrogen
2. Reduced blood flow to the endometrium
3. Over -exposure to testosterone
4. Permanent damage to the basal endometrium

17. Persistent thin endometrium should always be
evaluated for latent tuberculosis as incidence of
genital tuberculosis is very high in India
For all practical purposes,
completely damaged basal
endometrium cannot be
regenerated
Permanent damage to basal endometrium may occur
due to severe endometritis or due to vigorous
curettage following abortion

18. Endometrial Evaluation
• Functional biochemical
markers
• Histology
• Assessment by USG
• (TVS , 2D ,3D ,Doppler )
• MRI
• Hysteroscopy

19. LIFE HYSTEROSCOPY workshop at Lifecare Centre with
Prof. Osama Shawki on 14th & 15th December 2015

20. Endometrial Evaluation
• TVS provides a rapid
non invasive means
of assessing the
endometrium
• Thickest part of the
endometrium
should be measured

21. Endometrial Thickness
• Main advantage of measuring endometrial
thickness lies in its very high negative
predictive value
• Some authors have suggested that
endometrium of 6 mm or less is associated with
100% negative predictive value for conception
Fertil steril 1991,1994
The only limitation of endometrium thickness is that its
positive predictive value is poor

22. Higher uterine flow rates is associated with a
positive pregnancy outcome , while absent
diastolic flow is associated with no conception

23. Endometrial Implantation
ET 8 – 14 mm
BEST ENDOMETRIUM ON THE DAY OF HCG TRIGGER
ET > 16 mm or < 7mm
Is not associated with good prognosis

24. One of the most challenging problems faced in Rx of
infertility is to deal with thin endometrium
Neither there are clear cut remedies nor any
consensus regarding management of
thin endometrium

25. Attempts to Increase Endometrial Thickness
• Clear association between endometrial growth and the
circulating estrogen & progesterone levels.
• These hormones bind to the intracellular receptors and
the resulting proteins upregulate and downregulate
genes which influence implantation
• Today number of drugs and methods are
available to improve oestrogen level in the
endometrium and to increase blood supply to
basal endometrium.

26. For Anti oestrogenic effect of clomiphene
• Alternative drugs like Letrazole / Tamoxifen
• However, these drugs remain off – label for
ovulation induction and hence cannot be
recommended at present.

27. Addition of Oestrogen …. the next most logical
step to improve Thin Endometrium
• Good uterine blood
flow is very important
for endometrial
growth.
• Any resistance to blood
flow impairs growth of
glandular epithelium &
results in decrease in VEGF
which in turn further
causes poor flow to
endometrium
• Estrogen produces a
vasodilatory effect on
the uterine arteries
• RI, PI of uterine artery
drops with increasing
estradiol levels.
No pregnancy seen if the PI of uterine is > 3
Steer et al : Human Reproduction. 1990;5:391

28. The Famous Meta analysis on oestrogen use
Torres R.F, A Meta-Analysis. Fertil steril 2005; 84:S162-S163
• Most use oral estradiol 2mg
tds daily from day 2
• Few infertility experts
increases the dose in step
wise fashion
• 2mg/day for 3- 4th day
• 4 mg from 5th to 8th day
• 6 mg from 9th day
• The dose, the regimen
and type of oestrogen
used vary widely with
little consensus
Appropriate development of endometrium
was seen in good 70 – 80 % cases

29. High doses of vitamin E
Takasaki A et al ferpil . Stoni 2010
600 mg / day (200 mg tds ) orally daily
statistically significant improvement is seen in
ET in 52% patients following treatment when
compared to previous untreated cycle.
72% showed improved RA – RI and
20 % conceived.
Vitamin E improves growth of the glandular epithelium
improves vascularity and expression of VEGF

30. Oral L - arginine supplementation
improves uterine blood flow , endometrial
receptivity and implantation
• Nitric oxide donor
• Nitric oxide relaxes
vascular smooth
muscle of the
endometrium
Dose
1.5gms four times (6gms)
from Ist day till trigger.
• Improves RA-RI in 89%
of patients
• 67% patients developed
endometrium more than
8 mm
Takasaki et al 2010

31. Sildenafil citrate
Improves uterine blood flow
Phosphodiesterase
inhibitor, that prevents the
breakdown of cGMP &
augments the action of
nitric oxide on vascular
smooth muscle
along with oestrogen ,
leads to proliferation of
endometrial lining ,
regulate cell growth ,
angiogenesis and thus
facilitates implantation
25 mgm vaginally 4 times daily till trigger
larger studies are necessary to confirm their effectiveness

32. Pentoxifylline (Trental)
Tourgeman et al., 2001
• Xanthine derivative
• Primarily used in medicine as an antifibrotic agent
for treatment of Intermittent Claudication in pts of
peripheral arterial disease
• Thus tried to improve endometrial circulation
• Dose - 400 mgm/day for 5 days
• Results are inconclusive

33. Micronized low dose ASPIRIN
• Micronized low dose aspirin has been tried
left and right
• But no randomised trial is available in
literature to show that it is worth while !!

34. • Nitroglycerine patch can also be used to
improve uterine blood flow but is associated
with side effects like hypotension and
headache, so not used
• Lifestyle change
Smoking
Alcohol
Improve BMI
All this helps to improve vascularity of endometrium

35. Newer modality of treatment :
Granulocyte colony stimulating factor
(GCSF )
• Nobert Gleicher et al 2011 was the first to
use it in 4 patients with dramatic
improvement in ET
• Improves ET in patients with thin
endometrium especially when it is due to
destruction of subendothelial layer and
where other treatment for vasodilatation
have failed.
Gleicher et al Fertil 2011,95 (6)2123

36. Fertility and Sterility Vol 95, No 6, 2123
May 2011

37. Granulocyte colony stimulating factor
(GCSF )
• Can be given both intrauterine and subcutaneously
and also intravenously
If being used i/v to be diluted only in 5 % dextrose
and never in saline
• Is given with 1 ml insulin syringe 6 – 12 hrs before
HCG administration
• Comes as 300 mcg / ml

38. Granulocyte colony stimulating factor
• Growth spurt in
endometrial thickness can
be observed within 48 hrs
of GCSF administration
• How does G-CSF thicken
the endometrium in such a
short time interval is not
known
• Has a promising future but
needs more well planned
research to recommend it
as a standard treatment

39. Evaluation of the role G-CSF in thin endometrium
Study Dose of GCSF Duration of therapy Results
Nobert
Gleicher et al
2011
1 ml 30 MU
(300mcg)
2-7 days before embryo
transfer (ET)by ET catheter
Dramatic improvement in
endometrial thickness all
four patients conceived with
one intramural ectopic
pregnancy.
Y Kim et al
2012
1 ml 30MU
(300mcg)
On the day of hCG injection Significantly higher
endometrial thickness (85%
showed improvement),
implantation and ongoing
pregnancy rate
Maryam
Eftekhar
2014
1 ml 30 MU
(300mcg)
12th – 13th day of cycle but
repeated once more if
endometrial thickness below
7 mm within 48 – 72 hours.
No difference in endometrial
thickness
Chemical pregnancy rate and
clinical pregnancy rate were
found to be better
(39.30%vs, 14.30% &
32.10%vs. 12.00%
respectively )

40. Large confirmatory studies are necessary
before it can be recommended for
routine use
Empirical treatment
• LMWH
• Corticosteroids
• IVIG
• Intralipid is not effective ,hence not advocated

41. Neuromuscular electrical stimulation and
biofeedback therapy is another very recent
experiment to improve thin endometrium
More work need to be done

42. Endometrial Scratch
• First paper by Barash 2003 , subsequently
Narvekar 2010
Potdar 2012
Toukhy 2013
Cochrane meta analysis 2015 ,Nastri et al concluded
Both CPR & live birth rate
are doubled

43. Rationale of Endometrial Scratch
• Induces decidualization of the endometrium
• Releases cytokines , growth factor , macrophages
and dendritic cells
• endometrial injury Improves blood flow
• Recruit stem cells to the endometrium , thus
creating a partially new endometrium free of
epigenetic defects
Healing promotes inflamation
necessary for implantation

44. Endometrial Scratch
When to do it ?
• Done in the luteal phase of the cycle
preceeding the actual treatment cycle
ie 7 days prior to the onset of menstruation
• Studies have shown that if done in follicular
phase of index cycle there is no benefit
• Only the superficial layer is scratched using
rotational and in & out movement
Today most infertility experts have started doing it

45. What Tomorrow Holds !!!

46. Endometrial Reconstruction with
autologus Stem cell therapy and freshly
prepared Platelet Rich Plasma
Has gained considerable
attention and seems to provide
‘Break Through’ in reproduction
Yoshioka et al 2006
Chen et al 2011

47. Possible mechanism of action
• Evokes favourable inflammatory reaction
producing cytokines
• Secretes proteases which regulates
endometrial function and thus improves
implantation

48. Ideal candidates for Stem Cell Therapy
• Patients with persistent thin endometrium
with repeated implantation failure.
• Treated patients of tuberclosis with thin
endometrium
• Asherman syndrome grade III
Intra uterine and intravenous adminstration of
autologous stem cell & platelets , freshly isolated from
patient effectively improves embryo implantation
Yoshioka et al 2006
Chen et al 2011

49. Dr. Manjula Agnani (Padamshree)
Hyderabad
Personally communicated to Dr. sharda jain
• Autologous stem cells from bone
marrow in 4 cases of refractory thin
endometrium
• 3 cases responded in the same cycle with
endometrial thickness of 8 mm plus and
in one case delayed response was seen
after 6 weeks

50. Life care CENTRE
• We have used autologous stem cells therapy
for poor endometrium in 6 cases.
• In 4 cases endometrial growth was 8 mm plus
& 2 became pregnant
• 1 case had delayed response &
• 1 case showed 7mm endometrium but cycle
was canceled because CRP was strongly
positive & TLcounts were 25000.

51. To conclude ……
• Select the best seed
• Prepare the best soil
• Plant at the
appropriate time
• Taking a different
approach achieves a
pregnancy in many
cases that have failed
repeatedly

52. To conclude ……
Soil thickness of 7 mm is must
for achieving pregnancy
G-CSF, endometrium scratch &
stem cells therapy has a
promising future

53. Serenity Prayer !!!
God Grant me the serenity to accept the
things I cannot change ;
The courage to change the things I can ;
And
The wisdom to know the difference

54. Thank You