Dr. Shiuli Mukherjee
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Dr. Shiuli Mukherjee MD, Fellow in Reproductive Medicine Institute of Reproductive Medicine, Kolkata, India. Abnormal pinopode and cytokine expression affecting endometrial receptivity in idiopathic recurrent miscarriage. Introduction.

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Dr. Shiuli Mukherjee MD, Fellow in Reproductive Medicine

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Dr shiuli mukherjee md fellow in reproductive medicine

Dr. Shiuli Mukherjee

MD, Fellow in Reproductive Medicine

Institute of Reproductive Medicine, Kolkata, India

Abnormal pinopode and cytokine expression affecting endometrial receptivity in idiopathic recurrent miscarriage


Introduction

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


Dr shiuli mukherjee md fellow in reproductive medicine

HYPOTHES

IS

Impaired immunoregulatory atmosphere

of endometrium

Hampers endometrial receptivity

Altered embryo-endometrial cross talk

Improper implantation

Unexplained recurrent first trimester miscarriage


Dr shiuli mukherjee md fellow in reproductive medicine

SUMMARY OF EVENTS IN ENDOMETRIAL RECEPTIVITY

‘E2’ stimulates

‘P’ activates

Physiological

Biochemical

Immuno

modulatory

Genetic

expression

Adhesion

Molecules

HOXA 10

Trophinin

PINOPODES

Cytokines

NK cells

Receptive endometrium

Window of implantation ( 7th – 9th post ovulation day)


Implantation is biomarkers interplay

“Implantation is biomarkers’ interplay”

Co-expression with integrin & LIF

Nardo & Nikas et al and Aghajanova L, Stavreus-Evers et al Fert.Stert 2003


Future and facts

Future and Facts

Fact

Future

Failure of implantation due to deficient expression of different biomarkers

  • Pinopode

  • αvβ3 Integrin

  • LIF

  • L-selectin

    Acosta et al, 2000

  • To establish their role in pathogenesis of unexplained RSM in 1st trimester via alteration of endometrial receptivity


Objectives

Objectives

  • To asses the expression level of different implantation markers in endometrium of women with Idiopathic Recurrent Miscarriage

  • αvβ3 Integrin

  • Leukemia Inhibitory Factor (LIF)

  • L-Selectin

  • Pinopode

    and compare them with that of fertile women


Materials and methods

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.


Patient selection

Patient selection

  • Case ( n = 47)

    Women with past history of idiopathic spontaneous recurrent miscarriage

  • Control ( n = 39)

    Fertile women without previous pregnancy loss


Inclusion criteria

Inclusion criteria

  • Age between 24-35 years

  • Previous ≥ 2 miscarriages (<12wk)

  • Not on any kind of medication


Exclusion criteria

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)


Method

Method

  • TVS - folliculometry from 10th day of natural menstrual cycle

  • Endometrial biopsy done between 7th and 9th day of post ovulation

  • Serum Progesterone level estimation on day of biopsy


Tissue preparation assessment

Tissue preparation & assessment

  • Immunohistochemistry to asses cell surface expression of αvβ3 Integrin, LIF and L-selectin

  • Pinopodes observed under scanning electron microscope.

  • Endometrial dating by histopathology.

  • Statistical analysis by Statistica version 6


Pinopode expression

Pinopode Expression

Qualitative

Quantitative

  • 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.


Qualitative estimation of pinopode

Qualitative estimation of Pinopode

Developing

Fully developed


Quantitative estimation of pinopode

Quantitative estimation of Pinopode

Scanty (< 20%)

Abundant (>50%)


Result analysis

Result analysis

Unpaired student t test, mean ± SD


Comparison of biomarkers in endometrium

Comparison of biomarkers in endometrium

Mean fluorescing pixel area (%)

P < 0.001

P < 0.001

P < 0.001


Comparison of pinopode morphology

Comparison of pinopode morphology

Patientsnumber

Fisher’s exact test with Freeman-Halton extension P =.051


Comparison of pinopode numbers

Comparison of pinopode numbers

Fisher’s exact test with Freeman-Halton extension P < 0.01


Discussion

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


Discussion continued

Discussion continued..

  • Present study shows statistically significant difference in expression levels of

    • αvβ3 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)


Discussion continued1

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


Conclusion

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.


Acknowledgement

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


Hope for a new beginning

Hope for a new beginning…….

Thank you.


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