Treatment options for damaged endometrium

DAMAGED ENDOMETRİUM
TREATMENT OPTIONS
TEVFİK YOLDEMİR MD. BSc. MA. PhD.
tyoldemir
@YoldemirTevfik

Clinical and live birth rates in autologous and donor
fresh IVF-ET.
Human Reproduction, Vol.33, No.10 pp. 1883–1888, 2018

fresh Day 5/6 IVF-ET.

fresh Day 3 IVF-ET

frozen–thaw ET

frozen–thaw Day 5/6 ET

Ongoing pregnancy and live birth for women with
EMT ≤ 7 mm and EMT > 7 mm
Human Reproduction Update, 2014 doi:10.1093/humupd/dmu011

Clinical pregnancy for women with EMT ≤ 7 mm and
women with EMT > 7 mm

Female age and number of oocytes retrieved in
cases with EMT ≤ 7 mmversus EMT > 7 mm.
Mean age in women with EMT ≤ 7 mm was significantly higher (P , 0.001) and the mean number of oocytes
retrieved was significantly lower (P , 0.001) compared with the group with EMT >7 mm.

Causative factors, side effects and treatment of AS
and thin endometrium
Biomedicine & Pharmacotherapy 102 (2018) 333–343

thin endometrium
maximal EMT is ˂8 mm,
• when dominant follicles are
18 mm in diameter in
ovulatory cycles,
• or estrogen has been used
for endometrial preparation
for 20 days and serum
estradiol (E2) concentrations
maintained above 200
pg/ml in FET cycles.
Chin Med J 2015;128:3173-7.

Long-term estrogen treatment
• Estrogen treatment, in the form of 15–18 mg of estradiol valerate per
day, was given orally starting on the 2nd day of each menstrual cycle.
(Cyclo-progynova , 8-9 white tab/d)
• Thereafter, the dose of estrogen was adjusted to keep serum E2 >600
pg/ml.
• If serum E2 concentrations were not maintained above 600 pg/ml
with oral administration, 2–4 mg/d of intravaginal 17β-E2 (estrofem
tab) was added.
• Serum E2 concentrations and EMT were evaluated every 15–20 days
during the treatment, the goal being to increase the EMT to ≥8 mm.
Chin Med J 2015;128:3173-7.

Long-term estrogen treatment
• When the EMT had reached 8 mm, progesterone was injected
intramuscularly for 5 days and assisted reproductive cycles
started on the 2nd day of the subsequent withdrawal bleeding.
Chin Med J 2015;128:3173-7.

Growth hormone on pregnancy rates of patients
with thin endometrium
• Thin endometrium was defined as EMT ≤7 mm on the day of HCG
administration in their first IVF/ICSI cycle.
• daily GH (Norditropin SimpleXx 15mg/1.5 ml) subcutaneous injection
of 5 IU (0.15 ml/d)
• oral estradiol valerate (Cyclo Progynova) starting on day 3 of their
cycles until the 18th day and vaginal estradiol (Femoston, Abbott,
estradiol/dydrogesterone) 1 mg per day from 15th to 18th day.
• Estradiol valerate was administrated at a dosage of 2 mg twice daily
for the first 4 days, and 3 mg twice daily for the following days.
Journal of Endocrinological Investigation
https://doi.org/10.1007/s40618-018-0877-1

Growth hormone on pregnancy rates of patients with
thin endometrium
• 40 study vs 53 controls
• Progesterone supplementation was commenced on the 18th
day.
• Two grade II day 3 embryos were transferred on day 4 of
progesterone administration.
• Intramuscular injection of 60 mg progesterone daily
combined with 10 mg oral dydrogesterone twice daily as
luteal phase support.
• CP = GH 17/39 vs C 10/52 (SS) Journal of Endocrinological Investigation
https://doi.org/10.1007/s40618-018-0877-1

Growth hormone on pregnancy rates of patients with
thin endometrium
Journal of Endocrinological Investigation
https://doi.org/10.1007/s40618-018-0877-1

Follicular HCG endometrium priming for IVF patients
experiencing resisting thin endometrium
• Irregular cycling women received a depot Triptorelin 3.75 mg
injection the preceding cycle around day 21, and started the estrogen
replacement cycle after the period and minimum 14 days after the
depot injection.
• Regular cycling women started the estrogens on day-2 of their period.
• 17-beta estradiol starting dose was 4 mg per os for 3 days, then 6 mg
for 3 days, and then 8 mg onwards.
• On day-8 or 9 of the estrogen administration, and continuing 8 mg
estrogen per day, subcutaneous injections of 150 IU HCG were
initiated daily for 7 days. J Assist Reprod Genet (2013) 30:1341–1345
DOI 10.1007/s10815-013-0076-0

Follicular HCG endometrium priming for IVF patients
experiencing resisting thin endometrium
• After a week on HCG priming, (day-14 or 15) endometrial
thickness was checked with transvaginal ultrasound, and
hormone analysis was performed.
• HCG priming discontinued and the next day progesterone
administration was initiated for one extra day of the age of
the transferred embryos.
• The luteal phase support consisted of 8 mg of 17-beta
estradiol (in two doses); 600 mcg micronized progesterone (in
three doses).
• PR 9/17, DR 7/17 J Assist Reprod Genet (2013) 30:1341–1345
DOI 10.1007/s10815-013-0076-0

Human chorionic gonadotropin to frozen thawed
embryo transfer cycles
• 8 mg estradiol valerate from the second day of menstrual cycle and
continued at least for seven days.
• HCG (Pregnyl®) was administrated (150 IU, intramuscular) from the 8th
day of cycle.
• The HCG vial (1500 IU) was diluted 10 times and one was injected
every day.
• On the 12th-13th day trans-vaginal sonography was done.
• If endometrial thickness was proper, (at least 7mm) HCG stopped and
after 24 hr progesterone 100 mg intramuscular was injected for 3 days.
• CP 5/28
Int J Reprod BioMed Vol. 2016; 14. No. 1. pp: 53-56

Tamoxifen in Frozen–Thawed Embryo Transfers
• PCOS – Anovulation => 4 to 6 mg oral E2 valerate (Cyclo
Progynova) daily started on day 3 and continued for 10 days.
Then endometrial growth was monitored and serum levels of
luteinizing hormone, E2, and progesterone were measured.
The dose of subsequent E2 valerate was adjusted according to
the EMT, and the maximum dose was 8 mg/d.
Reproductive Sciences 2017 DOI: 10.1177/1933719117698580

Tamoxifen in Frozen–Thawed Embryo Transfers
• 20 mg tamoxifen (tamoxifen citrate tablets) daily for 5 days
since day 3 of menstrual cycle, accompanying with 1 mg/d of
intravaginal 17b-E2 (E2 tablets in Femoston; Abbott Biologicals
B.V) or 2 mg/d of oral E2 valerate on day 5 until the day of
ovulation.
• Human menopausal gonadotropin was given starting on day 8
up to the spontaneous ovulation or HCG injection

Autologous platelet-rich plasma (PRP)
• Platelet-rich plasma (PRP) is prepared from fresh whole blood
which is collected from a peripheral vein, stored in acid citrate
dextrose solution A (ACD-A) anticoagulant and processed to
increase platelets by separating various components of blood
• In conventional hormone replacement therapy (HRT) treatment
cycles, estradiol valerate (Cyclo Progynova) at 6 mg/d was given
on day 3 of menstrual cycle.The dosage was steadily increased
every 4 days, and the maximal dose was 12 mg/d.
Int J Clin Exp Med 2015;8(1):1286-1290

PRP
• PRP was prepared from autologous blood by a modified method of
Yamaguchi et al.
• 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.
Int J Clin Exp Med 2015;8(1):1286-1290

PRP
• It was infused into the uterus cavity immediately with Tomcat
catheter (0.5-1 ml).
• Endometrial thickness was re-assessed 72 h later. If the
endometrial thickness was not satisfied, infusion of PRP was
performed 1-2 times.
Int J Clin Exp Med 2015;8(1):1286-1290

Some resources and features of stem cells which
contribute in endometrium regeneration

The path which stem cells should to go in order to
cause its regenerative effects

‘’Cell sheet’’ transplantation techniques in rats
• Female green fluorescent protein (GFP) transgenic rats (SD-Tg
[CAG-EGFP] rats) age 3 weeks (n ¼ 13) were used to collect
endometrial cells for fabricating three-layer cell sheets
• female adult nude rats (F344/NJcl-rnu/rnu) age 9 weeks
(weight approximately 150 g) were used for all transplantation
experiments
Fertil Steril 2018;110:172–81

Human mesenchymal stem cells in spheroids
• Menstrual blood is noninvasive and easily available material for
isolation of endometrial MSC (eMSC).
• MSC in spheroids increased transplanted cell survival and
efficacy of stem cell therapy.
• 100 female rats underwent the induction of modeled
Asherman’s syndrome
• transplantation material (rat BM, eMSC monolayer, eMSC
spheroids) and delivery mode (vein or intrauterine injection).
Stem Cell Research & Therapy (2018) 9:50
https://doi.org/10.1186/s13287-018-0801-9

Human mesenchymal stem cells in spheroids
Stem Cell Research & Therapy (2018) 9:50
https://doi.org/10.1186/s13287-018-0801-9

A summary of the cell therapy to treat injured endometrium,
repair thin endometrium and its effect on fertility rate.

Granulocyte colony-stimulating factor (G-CSF)
• 10 RCTs, involving 1016 IVF-ET cycles (521 distributed to the G-
CSF group and 495 to the control)
• CPR, RR 1.89, 95% CI 1.53–2.33
• IR, RR 1.84, 95% CI 0.84–4.03
• Both uterine infusion and subcutaneous injection can produce
a substantial increase in CPR
• RIF - higher PR and IR in G-CSF group as compared to that in the
control, with the RRs (95% CI) 2.07 (1.64–2.61) and 1.52 (1.08–
2.14), respectively
Archives of Gynecology and Obstetrics
https://doi.org/10.1007/s00404-018-4892-4

Transvaginal perfusion of G-CSF in frozen ET program
• estradiol valerate tablet (2 mg) 6 mg daily and low-dose aspirin (80
mg) from the second day of the menstrual cycle.
• Ultrasonography was done from the 12th-13th day of cycle.
• uterine infusion of 300 microgram recombinant human G-CSF (300
microgram - Neupogen 30 MIU/0.5 ml- 30 MU = 300 microgram) by
the use of IUI catheter.
• After 2-3 days, the thickness of endometrium was measured again and
if it was at least 7mm, the patient received 100mg intramuscular
progesterone in oil (50 mg) for 3 days. Then 2 or 3, day-3 embryos
were transferred. If not, the second injection was done in GCSF group.
• 34 vs 34 CPR similar
Iran J Reprod Med 2014; Vol. 12. No. 10. pp: 661-666

G-CSF vs G-CSF with Endometrial Scratch (EMS)
• In G-CSF cycles, a natural cycle was used in patients with
normal ovulation; otherwise, an induced ovulation cycle was
used.
• Oral letrozole at a dose of 2.5–5.0 mg was administered each
day from day 3 to day 8, and intramuscular HMG at a dose of
75–150 IU was administered each day after day 12 if there
follicle development was poor in induced ovulation cycles.
• Follicle diameters were monitored by transvaginal ultrasound
starting on day 8 of the patient’s natural menstrual cycle or
induced ovulation cycles.
Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.12.006

• On the day that one follicle became dominant (almost 12× 12 mm in
diameter), intrauterine instillation with G-CSF was performed.
• An endometrial biopsy catheter was used to carry out EMS
(Endometrial Scratch).
• For G-CSF with EMS, an endometrial biopsy catheter was inserted
through the cervical orifice and advanced gently until it reached the
uterine fundus.
• Then, the inner piston of the device was withdrawn to create suction,
and the endometrium was lightly scratched once or twice up and
down on every wall of the uterine cavity. The entire procedure was
carried out gently and guided by abdominal ultrasound imaging.

• Then, 300 g of G-CSF (100 g/0.6 ml) was aspirated into a 2-ml
syringe, and an embryo transfer catheter (Laboratoire C.C.D.,
Paris, France) was introduced into the endometrial cavity.
• When the tip of the embryo transfer catheter made contact
with the uterine fundus, the contents of the syringe were
slowly injected into the cavity.
• Afterwards, the catheter was gently moved back after most of
the syringe contents had been injected into the uterine cavity.
• 14 G-CSF vs 13 G-CSF + EMS LBR similar

Intrauterine
perfusion
of G-CSF
on pregnancy
outcomes
in IVF or FET
cycles.

G-CSF vs control, outcome: endometrial thickness
Am J Reprod Immunol. 2017;e12701. doi.org/10.1111/aji.12701

G-CSF vs control, outcome: clinical pregnancy rate

G-CSF vs control, outcome: embryo implantation rate

G-CSF vs control, outcome: cycle cancelation rate

Granulocyte-colony stimulating factor
European Journal of Obstetrics & Gynecology and Reproductive Biology 214 (2017) 16–24

European Journal of Obstetrics & Gynecology and Reproductive Biology 214 (2017) 16–24

Sample size Calculation (G*Power3.1.9.2)
Live Birth Rate
• 20.2% → 27.8% 352 / 352 267 / 533 Fresh ET
• 31.7% → 40.6% 445 / 445 335 / 669 Fresh BT
• 23.7% → 28.4% 1486 / 1486 1120 / 2241 FET
• 26.2% → 30.2% 1557 / 1557 1162 / 2325 FBT
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
Take away messages
Confounding factors

Thank you for your attention.
TEVFİK YOLDEMİR MD. BSc. MA. PhD.
tyoldemir
@YoldemirTevfik

Treatment options for damaged endometrium

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