Thin Endometrium & Infertility(Part – II) , Treatment of endometrium , causes of thin endometrium, endometrium , ivf, stem cell therpay

1. Thin Endometrium
& Infertility
(Part – II)
Dr. Sharda Jain
Dr. Jyoti Agarwal
Dr. Jyoti Bhaskar

2. OUR TEAM

3. Healthy seed in not enough to get a
healthy sapling unless it grown on
fertile soil.
Similarly healthy embryo needs
receptive endometrium for successful
implantation.
Hard Facts

4. Optimum endometrium i.e. 7
mm preovulatory is must for
achieving pregnancy –
Management of This
endometrium is challenging
problem for infertility experts
There is no consensus regarding
management of
thin endometrium found at
the time of
ovulation induction in IUI &
IVF.
Treatment of
Thin endometrium in infertility

5. Important causes of poor endometrium
growth during ovulation induction are:
Endometrial resistance to oestrogen.
 Reduced blood flow.
 Over -exposure to testosterone.
Permanent damage to the basal
endometrium
Causes of Thin Endometrium

6. Based on aetiology, number of
drugs/methods
has been used with aims of
improvement
oestrogen level in endometrium and
increase
blood supply to basal endometrium.
Principle of Treatment of
thin Endometrium in infertility

7. Treatment strategy
For Anti oestrogens
effect of clomiphene

8. In the group of patients where clomiphene
induction is associated with thin
Endometrium,
LETROZOLE
TAMOXIFEN
Can be alternative drugs
Use Alternative drugs to
clomiphene induction
Letrozole / Tamoxiten

9. However, these drugs remain
off – label for ovulation
induction and hence cannot
be recommended at present.
Use for ovulation induction with
LETROZOLE / TAMOXITEN
have the advantage of avoiding
peripheral anti estrogenic effects.

10. OESTROGEN – is second
alternative
In this group of patients, addition of
oestrogen is seen as the logical step in
combating antiestrogenic effect on
endometrium.
However, the dose, the regimen and type
of oestrogen used vary widely with little
consensus to the treatment approach.

11. In a meta-analysis done by Torres RF et al
examined the use of pure ethinyl estradiol
(EE) for treatment of thin endometrium,
observed that use of Ethinyl estradiol 0.02-
0.05mg/day given from 7th day of cycle for 5
days, does improve the endometrial thickness
in comparison to patients where only placebo
was used.
Torres R.F, A Meta-Analysis. Fertil steril 2005; 84:S162-S163
The Famous Meta analysis
On oestrogen use

12. Other oestrogen preparation and
dose schedule reported in
literature are :
Conjugated equine
Oestrogen :
0.625 mg from day 7TH
FOR 5 DAYS.
Transdermal ethinyl
Oestradiol :
4 mg / day from day 8th
till
the day of ovulation
Vaginally administered
Local estrogen :
To avoid the first pass of
systemic oestrogen

13. OESTROGEN USED
VAGINALLY
 Kadir Cetinkaya et al used vaginally
administered local oestrogen 25mcgms from
4th
day for 15 days in CC induced cycle. They
reported significant increase in ET on the
day of ovulation (7.6 +/-1.4 mm vs 8.3+/-2.1
mm) than the group where only CC was
used, but there was no change in pregnancy
rate.
Cetin kaya k e al Ja. Tuk . Ger. Gynaecol. Assoc 2012 , 13CB), 157-61

14. ORAL OESTROGENS
Oral oestrogens are now routinely used for
preparation of endometrium for frozen embryo
transfer, where previous IVF failure was thought
to be due to thin endometrium.
Dose schedule is different from fresh cycle. Most
use oral estradiol 2mg thrice daily from day one
for 12 days.
The appropriate development of endometrium in
seen in good 70 – 80 % cases

15. Few IVF experts use step wise increased
dose of oestradiol, 2mg/day from Ist to
4th
day , 4 mg from 5th
to 8th
day and 6 mg
from 9th
to 12th
day of cycle and reported
better ET development.
Oestrogen is also found to improve
blood circulation to radial artery which is
evident by improved flow in radial
artery.
ORAL OESTROGENS

16. Vitamin EVitamin E the dose of 600 mg / day (200 mg three
times daily ) orally given throughout the menstrual
cycle to improve ET.
Akihisa Takasaki et al observed adequate ET in 52%
patients following treatment. 72% showed improved
RA – RI and 20 % conceived. Each of these parameters
registered statically significant improvement when
compared to previous untreated cycle.
Vitamin E improves growth of the glandular
epithelium and number of blood vessels VEGE protein
expression.
Takasaki A et al ferpil . Stoni 2010, 93 (6) 1851 -8

17. L arginine treatment :
Akihisa Takasaki et al tried L arginine in patient
with thin endometrium at the dose 1.5gms
four times (6gms) from ist day till the day of
hCG injection. It improved RA-RI in 89% of
patients and 67% patients developed
endometrium more than 8 mm this
difference was statistically significant when
compared to previous cycle in these patients.
Takasaki A et al ferpil . Stoni 2010, 93 (6) 1851 -8

18. SILDENAFIL CITRATE
Sildenafil citrate, a type 5 – specific
phosphodiesterase inhibitor, augments the
action of Nitric Oxide on vascular smooth
muscle.
It is thought to improve uterine blood flow
and along with oestrogen -- leads to
oestrogen induced proliferation of
endometrial lining.

19. Tumor suppressor factor (p53), Plasminogen
activator inhibitor 1 (PAI – 1), and Vascular
endothelial growth factor (VEGF) need to
produced necessary to digest the endometrial
cellular matrix to regulate cell growth and
angiogenesis to facilitate implantation.
Sildenafil citrate markedly enhanced p53 ,PAI – 1
with increased VEGF.
Sildenafil Citrate

20. Many studies have been
conducted to evaluate the role of
sildenafil to improve THIN
ENDOMETRIUM in patients of
infertility

21. Study Dose
of
Silden
afil
Duration of
therapy
Mode of
administ
ration
Results
Takasaki et al 2 100 mg Ist day till day of
ovulation
Intravaginal 92% patients showed
improvement in endometrial
thickness andd RA – RI
Intravaginal route reduces side
effects llike headache and
hypotension.
Firouzabadi et al
6
50 mg Ist day till 45-72 hours
prior to embryo
transfer
Oral Endometrial thickness and
triple line pattern significantly
higher with sildenafil and
estadiol valerate as compared
to estradiol alone clinical
pregnancy rate was higher but
not significant
Malgorzata
Jerzak et al7
2.5 mg X
four
Times a
day
3-6 days Intravaginal
Suppostory
Endometrial thickness was
significantly increased Dose
independent reduction in NK
cell activity Successful use of
sildenafil in two infertility
patients with Asherman

22. Pentoxifyline• Pentoxifyline, a xanthine
derivative, which is primarily used
in medicine for treatment of
Intermittent Claudication resulting
from peripheral arterial disease
has also been tried to increase
endometrial circulation--- with no
conclusive result

23. Micronized low dose
ASPIRIN
Micronized low dose aspirin
has been tried left and right
But no randomised trial is
available literature to show
whatever it is worth white !!

24. GRANULOCYTE COLONY
STIMULATING FACTOR
(GCSF )-- A new promise
G-CSF has shown potential of improving
ET in patients with poor endometrial
growth especially when it is due to
destruction of subendothelial layer
where other common treatment for
vasodilatation have failed.
Gleicher in et all Fertil . Senl 2011, 95(6)2123

25. Norbert Gleicher et al 2011 was the first to use it
in four patients with dramatic improvement in
ET.
Various reported studies are shown in next slide
but this is still in experimental stage and it
needs more well planned research with large
sample size to be able to recommend it as a
standard treatment.
Granulocyte colony stimulating
factor (GCSF ) new promise
Gleicher in et all Fertil . Senl 2011, 95(6)2123

26. Evaluation of the role G-CSF in thin endometrium
Study Dose of GCSF Duration of therapy Results
Nobert
Gleicher et al
2011 8
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 ) Not
statistically significant

27. NEUROMUSCULAR ELECTRICAL
STIMULATION and biofeedback
therapy is another very recent
experiment on improvement of poor
endometrial growth.
However , more work need to be due.

28. Endometrial scratch
Few randomized controlled trial
has shown that endometrial
scratching in the luteal phase of
one cycle prior to IVF CYCLE
 INCREASES PREGNANCY RATE

29. RATIONALE of
endometrial scratch
Tissue injury procedures like
endometrial biopsy or hysteroscopy
in the cycle prior to IVF treatment
induces stem cell differentiation
and increases the endometrial
receptively during the IVF treatment
cycle.
Most expert doing IVF & IUI have started doing it.

30. Endometrial Reconstruction
with Stem cell therapy
 Ideal candidates
The patients with persistent thin
endometrium with repeated
implantation failure.
Treated cases of tuberclosis with thin
endometrium
Asherman syndrome grade III are the
patient who need it most

31. Recent case report of endometrial
reconstruction using autologous
bone Marrow stem cells followed by
conception by IVF in two patients
has gained considerable attention
and seems to provide ‘break
through’ for conception in IVF cycle.
Stem cell and thin
endometrium

32. Life care IVF
 We have used autogous stem
cells therpy along with use of
stem cells in locally in the
endometrium in 2 cases.
 In both cases endometrial
growth was 8 mm plus &
pregnancy occurred in one

33. Dr. Manjula Agnani (Padamshree)
from Hyderabad
Personal communication to Dr. sharda jain
Autologous stem cells therapy from bone
marrow was used in 4 cases of refractory
thin endometrium
All four responded with endometrial growth
8 mm plus.

34. ConclusionEvaluation and detection of any endometrial
abnormality is one the cornerstone in the
management of infertility
Optimum endometrium thickness i.e. 7 mm
preovulatory is must for achieving pregnancy
Various modalities have been studied for
improving the endometrium (thickness and
vascularity)

35. -- But treatment modalities for
achieving adequate endometrium
this are still evolving
G-CSF, endometrium scratch &
stem cells therapy are new entry
Conclusion

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