Granulocyte Colony Stimulating Factor (GCSF)- What, How and When to use in IUI Hard facts

1. Granulocyte Colony Stimulating
Factor (GCSF)- What, How and
When to use in IUI
…Caring hearts, healing hands
Thin Endometrium
Dr. Sharda Jain
Dr. Jyoti Agarwal

2. Our PPts on RECURRENT MISCARRIAGE
is Uploaded on slideshare.net
• Thin Endometrium & Infertility (Part – I)
http://www.slideshare.net/LifecareCentre/thin-endometrium-infertilitypart-i-dr-sharda-jain-life-care-centre
• Thin Endometrium & Infertility (Part – II)
http://www.slideshare.net/LifecareCentre/thin-endometrium-infertilitypart-ii-dr-sharda-jain-life-care-centre
• Thin Endometrium & Infertility
http://www.slideshare.net/LifecareCentre/thin-endometrium-infertility
• Thin Endometrium Granulocyte Colony Stimulating Factor
(GCSF)- What, How and When to use in IUI

3. Hard facts
Success in each IUI cycle:
*with clomiphene +IUI=8%
• With CC+GONADOTROPHIN=IUI- 9-12%
• pure Gonadotropins cycle- 20%
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4. I.U.I success depends on
• Good eggs
• Good sperms
• Patent fallopian tubes
• Good endometrium- dialogue between embryo
and endometrium is very important.
• Endometrial function and endometrial
receptivity are major limiting factors in
establishment of a pregnancy
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5. Causes of thin endometrium
• Endometrial resistance to circulating
estrogen
• Reduced blood flow to the endometrium
• Over -exposure to testosterone
• Permanent damage to the basal
endometrium
• Infection like MTB
• Asherman syndrome
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6. Persistent thin endometrium
• Evaluate for STB- 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
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7. Endometrial Evaluation
• Assessment by USG
(TVS = 2D )
• Hysteroscopy
• Histology
• MRI
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8. TVS
• Rapid non invasive means of assessing the
endometrium
• Thickest part of the endometrium should be measured
• Endometrium of 6 mm or less is associated with 100%
negative predictive value for conception Fertil steril
1991,1994
• ET 8 – 14 mm is best endometrium on day of HCG
trigger
• ET > 16 mm or < 7mm Is not associated with good
prognosis

9. Modalities to increase endometrium
1. Oral estradiol 2mg tds
2. High doses of vitamin E (200mg TDS)
3. Oral L - arginine supplementation (1.5gms
QID) Takasaki et al 2010
4. Sildenafil citrate (25mg TDS- vaginally)
5. Pentoxifylline (400mg/day)
6. low dose Aspirin (75mg/day)
7. Nitroglycerine patch
8. G CSF
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10. G-CSF
• Glycoprotein, growth factor and cytokine
 Sources- endothelial cells, monocytes, macrophages, and
fibroblasts
 Reproductive tract: follicular, granulosa cells, endometrial cells,
and cells from decidual, placental and various fetal tissues
• Promotes neutrophil proliferation and maturation
• Produced by recombinant DNA technology from E coli into which
the human G-CSF gene has been inserted.
Human Reproduction Vol.23, No.9 pp. 2001–2009, 2008 …Caring hearts, healing hands

11. G-CSF
G-CSF involved in a wide variety of reproductive functions:
implicated in normal ovulation
maintaining healthy endometrium (successful implantation and
further development of embryo)
Useful biomarker of oocyte competence before fertilization.
improve implantation rate and successful pregnancy outcome in
infertility, IUI and IVF procedures
Enhancing endometrial receptivity ??
Indian J Med Res. Oct 2011; 134(4): 440–446.; Human Reproduction,
Vol.28, No.1 pp. 172–177, 2013

12. Absorption: Not absorbed orally. Rapidly absorbed following s.c.
injection/ infusion into uterine cavity and peak serum concentrations
are generally attained within 4-5 hours.
Distribution: Rapidly distributed, highest concentration in bone
marrow, adrenal glands, kidney and liver.
Half-lifeis approximately 3.5 hours, both with SC or IV injection.
Pharmacokinetics
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13. G-CSF
Recruitment of
neutrophils
VEGF
Growth of new blood
vessels
Blood supply
Vascular remodeling,
endometrial proliferation,
uterine gland
transformation
Endometrial
decidualization &
thickening

14. Role of G-CSF in Infertility
• Role of G-CSF in infertility patients with
chronically Role of G-CSF in infertility
patients with chronically thin
endometrium in endometrium Role of
G-CSF in infertility patients with
chronically thin endometrium
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15. Effect of G-CSF on Endometrium
•In endometrium: G-CSF is secreted apically in
polarized epithelial cells.
•G-CSF has been proposed as a treatment for
implantation failure and repeated
miscarriages.
•A growth spurt in endometrial thickness can
be observed within 48 hours of G-CSF
administration.
Journal of Endocrinology (2011) 210, 5–14; Human Reproduction, Vol.24, No.11 pp. 2703–2708, 2009; Human Reproduction
Vol.20, No.6 pp. 1439–1446, 2005

16. Ongoing RCT
• NCT01202643: whether, and to what
degree, endometrial infusion with
G-CSF, is able to expand chronically
thin endometrium, which is resistant to
standard therapies?
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17. Case report
Fertility and Sterility Vol. 95, No. 6, 2123. e13-e17, May 2011

18. Case Report
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19. A pilot cohort study of granulocyte
colony-stimulating factor in the
treatment of unresponsive thin
endometrium resistant to standard
therapies
Human Reproduction, Vol.28, No.1 pp. 172–177, 2013 …Caring hearts, healing hands

20. Materials and Methods
• Study design: prospective observational cohort pilot study
over 18 months
• Patients: 21 infertile women with endometrium < 7 mm
on the day of hCG administration in 1st IVF cycle
– Previous treatment including oral and vaginal thinly
estradiol (E2: 2 mg, per so BID and 1 mg per vagina TID)
and sildenafil citrate (25 mg per vagina QID)

21. Procedure
• IUI catheter
• 1-ml insulin syringe
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22. •Ovulation induction, trigger with hCG 10,000 IU: ≧1 follicle ≧
19 mm
•Diagnosis of unresponsive thin endometrium: < 7mm by
ultrasound on the day of hCG administration
•G-CSF endometrial infusion:
1.300mcg/1ml (Filgastrim) approximately 6-12 h before
hCG administration
2.Repeated G-CSF infusion if endometrium <7mm on day
of ovum pickup
***Protocols used:
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23. Results
• All patients
underwent
embryo transfer
(EM ≥ 7mm).
• The clinical
pregnancy rate
was 19.1%.
Significant

24. How to use in IUI?
• Ovulation induction with CC or Gonadotropins
• hCG 10,000 IU ≥1 follicle ≥ 20 mm
• Diagnosis of unresponsive thin endometrium: < 7 mm by
ultrasound on the day of hCG administration
• G-CSF endometrial infusion: 300 mcg/1 ml approximately 6-12
h before hCG administration
• Endometrium has been documented to grow between 1-4 mm after
the infusion.
• Many studies ongoing…
…Caring hearts, healing hands

25. Procedure
• IUI catheter
• 1-ml insulin syringe
• Lithotomy position
• Partially full bladder

26. 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

27. 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

28. 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 )

29. Other Indications
• For the treatment of thin endometrium.
• As a treatment option in patients with
recurrent miscarriages.
• In repeated embryo implantation failures in
IVF
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30. Condition Dose
Route of
administration
Non Responsive Thin
Endometruim
•300mcg/1ml approximately 6-
12 h before hCG
administration
• Repeated G-CSF infusion if
endometrium <7mm on TVOR
day
G-CSF
endometrial
infusion
Unexplained recurrent
miscarriage
1mcg/kg/day From 6th day of
ovulation till the menstruation
or till the 9th week of
pregnancy
SC
Recurrent implantation
failure
GCSF 60mcg /day from the
day of transfer to the beta
HCG test day
SC

31. Conclusion
• G-CSF play important role in reproductive functions like
ovulation and embryo implantation.
• Infertile women with persistently thin endometrium may
significantly benefit from G-CSF.
• Data show that G-CSF may be effective in the treatment of
unexplained RM and RIF.
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32. ADDRESS
11 Gagan Vihar, Near Karkari Morh
Flyover, Delhi - 51
Helpline
9650588339,
9599044257
011-22414049, 011-22058865
WEBSITE :
www.drshardajain.com
www.lifecarecentre.in
www.lifecareivf.com
www.globalstemgenn.com
www.lifecareaesthetics.com
E-MAIL ID
Sharda.lifecare@gmail.com
Lifecarecentre21@gmail.com
info@lifecareivf.com
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