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Dr. Shiuli Mukherjee MD, Fellow in Reproductive Medicine Institute of Reproductive Medicine, Kolkata, India.

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Presentation on theme: "Dr. Shiuli Mukherjee MD, Fellow in Reproductive Medicine Institute of Reproductive Medicine, Kolkata, India."— Presentation transcript:

1 Dr. Shiuli Mukherjee MD, Fellow in Reproductive Medicine Institute of Reproductive Medicine, Kolkata, India

2 Introduction  Recurrent spontaneous miscarriage (RSM) represents most common complication of reproductive failure  60–70% remains unexplained  Impaired immunoregulatory atmosphere of endometrium may be a contributing factor Raghupathy R et al, Immunology Today,1997

3 Impaired immunoregulatory atmosphere of endometrium Hampers endometrial receptivity Altered embryo-endometrial cross talk Improper implantation Unexplained recurrent first trimester miscarriage HYPOTHESISHYPOTHESIS

4 SUMMARY OF EVENTS IN ENDOMETRIAL RECEPTIVITY Physiological BiochemicalImmuno modulatory Genetic expression PINOPODES Adhesion Molecules Cytokines NK cells HOXA 10 Trophinin ‘E2’ stimulates‘P’ activates Receptive endometrium Window of implantation ( 7 th – 9 th post ovulation day)

5 “Implantation is biomarkers’ interplay” Apposition Pinopode Adhesion Integrin ( αvβ3) L-selectin Invasion LIF cytokine Co-expression with integrin & LIF Nardo & Nikas et al and Aghajanova L, Stavreus-Evers et al Fert.Stert 2003

6 Future and Facts Fact Future Failure of implantation due to deficient expression of different biomarkers  Pinopode  α v β 3 Integrin  LIF  L-selectin Acosta et al, 2000  To establish their role in pathogenesis of unexplained RSM in 1 st trimester via alteration of endometrial receptivity

7 Objectives  To asses the expression level of different implantation markers in endometrium of women with Idiopathic Recurrent Miscarriage  α v β 3 Integrin  Leukemia Inhibitory Factor (LIF)  L-Selectin  Pinopode and compare them with that of fertile women

8 Materials and methods Prospective Case-control study August 2009 to July 2010 Institute of Reproductive Medicine, Kolkata and IIMST, Kharagpur, India Approval obtained from the institutional ethical committee and written consent taken.

9 Patient selection  Case ( n = 47) Women with past history of idiopathic spontaneous recurrent miscarriage  Control ( n = 39) Fertile women without previous pregnancy loss

10 Inclusion criteria  Age between years  Previous ≥ 2 miscarriages (<12wk)  Not on any kind of medication

11 Exclusion criteria  Autoimmune defects (APLA-Anti cardiolipin and anti lupus antibody)  Endocrine causes ( thyroid function test)  Chromosomal defect (karyotyping)  Coagulopathy ( P/H or F/H of thrombophilia)  Infectious disease  Uterine malformation ( HSG/hysteroscopy)  Sperm defects (DNA fragmentation)

12 Method  TVS - folliculometry from 10 th day of natural menstrual cycle  Endometrial biopsy done between 7 th and 9 th day of post ovulation  Serum Progesterone level estimation on day of biopsy

13 Tissue preparation & assessment  Immunohistochemistry to asses cell surface expression of α v β 3 Integrin, LIF and L-selectin  Pinopodes observed under scanning electron microscope.  Endometrial dating by histopathology.  Statistical analysis by Statistica version 6

14 Pinopode Expression QualitativeQuantitative  Developing - Small, smooth, naked, with short microvilli.  Fully developed – large, smooth, with/without small wrinkles.  Regressing - wrinkled surface, deflated ball Percentage of endometrial surface occupied  Abundant - > 50%  Moderate – 20-50%  Scanty - < 20% Mean values of 30 randomly selected fields taken Nikas et al, 1995,1999.

15 Qualitative estimation of Pinopode Developing Fully developed

16 Quantitative estimation of Pinopode Scanty (< 20%) Abundant (>50%)

17 Result analysis Clinical characteristicsPatient with RSM ( n= 47 ) Control ( n= 39 ) Age ( years )29.97± ±3.5 BMI (kg/m 2 )26.83± ±4.1 Day of EB22.08± ±1.03 Histopathology datingMid-secretory Progesterone (ng/ml)11.28± ±1.39 Unpaired student t test, mean ± SD

18 Comparison of biomarkers in endometrium P < 0.001

19 Comparison of pinopode morphology Fisher’s exact test with Freeman-Halton extension P =.051

20 Comparison of pinopode numbers Fisher’s exact test with Freeman-Halton extension P < 0.01

21 Discussion  Few studies have demonstrated correlation between unexplained recurrent miscarriage and expression of cytokines. Cork et al 1999, Laird & Tuckerman et al,2003  Relation with pinopode not been discussed thoroughly Aghajanova L et al,2003, Nardo LG et al, 2003  Nothing conclusive had yet been achieved

22 Discussion continued..  Present study shows statistically significant difference in expression levels of  α v β 3 Integrin ( P <0.001 vs NS in Tuckerman et al, 2006 )  LIF ( P <0.001 similar to Cork et al, 1999 )  L-selectin ( P <0.001 ≈ Kruse C.et al 2003, Foulk R.A. et al, 2007)

23 Discussion continued..  Pinopode expression in RSM  Morphological comparison – no significant difference ( P = 0.051)  Comparison of numbers – had significant difference ( P < 0.001) Other studies have shown correlation in unexplained infertility, endometriosis, PCOs Aghajanova L et al,2003

24 Conclusion  Expression of cytokines, pinopodes and adhesion molecules seem to be deficient in recurrent miscarriage group.  A combined protocol of biomarkers like integrin, pinopode and LIF could have a good predictive value of endometrial receptivity in idiopathic recurrent miscarriage.

25 Acknowledgement  Prof. (Dr.) B.N.Chakravarty  Prof. K. Chowdhury  Prof. ( Dr.) A.Hazra  Dr. S. Ghosh  Ms. P. Banerjee  Dr. R. chatterjee  Dr. S. Sharma  Dr. S. Rajani

26 Hope for a new beginning……. Thank you.


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