1. Endometrial biopsy in subfertile women undergoing intrauterine insemination (IUI) cycles improves pregnancy rates
Tumanyan A, Tchzmachyan R,
Grigoryan H, Hambartsoumian E.
Fertility Center
Yerevan, Armenia

2. Background Fertility Rate
Implantation is a major challenge in human reproduction.
Fertility Rate
A healthy young woman 20-22%
IVF - 25%-35%
3/4 embryos are not implanting successfully.
A healthy young woman has approximately a 20% chance to achieve a successful pregnancy with each menstrual cycle.
Even when embryos are to be of high quality implantation rates remain around 25%-35%
Thus, implantation failure is a common experience since the majority of embryos do not to implant successfully.
The European IVF-monitoring program 2005

3. Background Uterine factors: Major causes of implantation failure
thin endometrium,
poor endometrial receptivity
in the recent years among the various potential causes of implantation failure, uterine factors such as thin endometrium, poor endometrial receptivity, have received the most attention

4. Background Endometrial receptivity can be modulated by
Modulation of endometrial receptivity
Endometrial receptivity can be modulated by
A. biological factors
Cytokines
Growth factors
Mechanical factors
Endometrial scratching (biopsy)
It has been shown that endometrial receptivity could be modulated by a multitude of biological and even mechanical factors, such as endometrial scratching.

5. Background Biopsy stimulates the uterus’ receptivity Endometrial
local injury
Inflammation
white blood cells
growth factors
cytokines
Thus, recently it has been shown that local injury of the endometrium produces an inflammatory reaction resulting in increased white blood cells (leukocytes such as macrophages) which secrete growth factors and cytokines. These substances regulate blastocyst implantation and placental development. This stimulates the uterus’ receptivity to the embryo and increases the success rate of live birth.
blastocyst implantation
placental development

6. Background Biopsy of the endometrium in IVF patients:
Clinical studies in IVF patients
Biopsy of the endometrium in IVF patients:
Doubles the rates of implantation
Doubles the rates of pregnancy
In clinical trials it was demonstrated that local injury of the endometrium during a spontaneous menstrual cycle doubled the rates of implantation and pregnancy in IVF patients

7. Background Endometrial biopsy – IUI - ?
Clinical studies in IUI patients
Endometrial biopsy – IUI - ?
However, studies on the use of endometrial injury in intrauterine insemination (IUI) cycles are not available.

8. Objective To investigate the effect of endometrial
biopsy on the clinical outcomes of IUI
This study attempted to investigate whether the use of endometrial injury affects the clinical outcomes of IUI

9. MATERIAL AND METHODS Patients
Subfertile women with infertility of unknown reason
Study period:
For this purposes we recruited subfertile women with infertility of unknown reason who apply to our Fertility Center from time period of

10. MATERIAL AND METHODS Study design 94 patients randomisation
Group A (47)
Group B (47)
endometrial biopsy
mock  biopsy
Following is the study design
94 patients were randomly divided into two groups. Subjects of Group A underwent endometrial biopsy in the cycle preceding the IUI, while group B subjects underwent mock endometrial biopsy at the same day of previous cycle. COH and IUI we started on the next cycle, Overall up to 4 cycles were performed if patients were not pregnant
4 cycles of COH
and IUI
4 cycles of COH
and IUI

11. MATERIAL AND METHODS Protocol hCG 5000 IU IUI Biopsy/ mock Menopour
Didrogesteron
CC 50 mg
Our protocol included a one time procedure of local injury of the endometrium or mock biopsy on day 20 of the menstrual cycle that precedes a COH + IUI treatment. Both endometrial sampling and mock biopsy were performed using a "Pipelle" biopsy catheter.
Starting from day 3 of next cycle all patients received the same treatment: stimulation of ovulation by CC and gonadotropins and IUI, according to our standard protocols. If the pregnancy did not occur patients continue receiving COH and IUI without additional endometrial biopsies.  
D1 d d d d 13 d14…………days of cycle

12. MATERIAL AND METHODS Inclusion criteria Women
Infertility of unknown reason
Infertility > 2 years
N hormonal and anatomical status
history of regular menstrual cycles
< 38 y old
Male
N spermogramm.
an accent was made on rigorous definition of the inclusion criteria:
In women 1) age less than 38 years, 2) Infertility during 2 years or more in the absence of hormonal and anatomical disorders 3) history of regular menstrual cycles
in male: normal sperm quantity and quality

13. Main outcomes Pregnancy rate (per cycle) after COH and IUI
Cumulative pregnancy rate after 4 attempts of COH and IUI
Pregnancy complications

14. Secondary outcomes Endometrial thickness
Histological pattern of endometrial tissue

15. Group t-test, Student’s t-test
Statistics
Group t-test, Student’s t-test
P < 0.05

16. RESULTS Age (years) 28.2 ± 1.01 27.7 ± 0.9 NS
Demographics and Clinical data
Group A Group B P-value
Age (years) ± ± NS
Infertility (years) ± ± NS
BMI (kg/m2) ± ± NS
Motile sperm count (mln) ± 12, ± 19,2 NS
Age of subjects, duration of infertility, body mass index, basal hormone levels and sperm parameters were comparable between the two groups

17. RESULTS Secondary outcomes Endometrial thickness (mm) 9,6 ± 0,6
9,9 ± 1,6 NS
Complication from biopsy:
- infection,
- high T,
- bleeding,
- severe cramping
None
none
N/A
Also Endometrial thickness was not different between the two groups in all cycles.
There were no any complication related to the procedure of endometrial samplings or mock sampling

18. Histological findings (Group A)
Secondary outcomes
Histological findings (Group A)
Histological pattern %
-Small Polyp(s)
36.4
-Glandular Hyperplasia
29.7
-Chronic Endometritis
-Luteal phase defect
44.6
Histological data shown on this table Suggests that at least in part the cause of the infertility may be attributed to endometrial factors, invisible during transvaginal ultrasonography

19. Effect of endometrial biopsy in subfertile
RESULTS
Main outcome
Effect of endometrial biopsy in subfertile
women undergoing COH and IUI
Group A
Group B
P value
Cumulative pregnancy rate
Cumulative live birth rate
27/47
(55.3%)
20/47
(42.5%)
18/47
(38.3%)
11/47
(23.4%)
< 0.05
According to Main outcome of this study there is a significant difference in in terms of pregnancy rate between two groups. This, the cumulative clinical pregnancy rate was 55.3% in group A while it was only 38.3% in group B (p<0.05)
Accordingly the live birth rate was 42.5% in group A while it was 23.4% in group B (p=0.024)
As one can see “take home baby’s” rate in a group of patients with endometrial biopsy is almost twice as much as in a group B.
Fertility Center Yerevan Armenia

20. Pregnancy rate (%) per cycle after endometrial biopsy
RESULTS
Main outcome
Pregnancy rate (%) per cycle after endometrial biopsy
P<0.05
It is worthy to note, that the difference in clinical pregnancy between two groups was observed only on the first IUI but not on the 2nd 3rd and 4th cycles. Thus, clinical pregnancy rate in 1st IUI cycle after biopsy in group A was 29.7% while in group B only 14.8%.

21. The prevalence of pregnancy rate in relation to the IUI cycles
RESULTS
Main outcome
The prevalence of pregnancy rate in relation to the IUI cycles
1st IUI
51.8%
2nd IUI
20.8%
3rd
14.8%
4th
Indeed when one look at the data within the group of pregnant women more than 50 % of all pregnancies occurred on the first after the endometrial biopsy cycle.

22. Complications of pregnancy
RESULTS
Main outcome
Complications of pregnancy
Group A
Group B
P value
Abortions:
- Early Abortions
- Late abortions
7/ (25.9%)
6/27 (22,2%)
1/ (3.4%)
6/18 (33.3%)
0/18
<0.05
N/A
Interestingly the abortion rate was also significantly less in a group A compared to group B.

23. CONCLUSIONs
Endometrial biopsy prior to an IUI cycle significantly improves the rates of clinical pregnancy and live birth in women with infertility of unknown reason
Thus, results of our study suggest that local injury to the endometrium prior to an IUI cycle improves the rates of clinical pregnancy and live birth in women with infertility of unknown reason.

24. THANK YOU! www.FertilityCenter.am
Improving implantation continues to pose a major challenge to clinicians working in the field of human reproduction.