EVIDENCE FOR GENETIC SIGNATURE OF ADENOMYOSIS / ENDOMETRIOSIS :

First report of adenomyosis in monozygotic twin fetuses

SEUD, 2015

J.Martinovic, D. Rambaud, J. Gogusev, C. Bergeron, A.Benachi

Fetal Pathology Department Hôpital Antoine Béclère

ENDOMETRIOSIS: BACKGROUND

* affects approx. 10% of the female population * F increases up to 35-60% in women with pain

and/or infertility * one of the most common human diseases * still unknown etiology

ENDOMETRIOSIS: PATHOGENESIS

•  Retrograde menstruation implants (Sampson, 1927) •  Vascular migration of endometrium (Sampson,

1927) •  Metaplastic theory (Nissole, 1997) •  Defects of embryogenesis (Signorille, 2010) •  Circulating stem cells’ ectopic impl. (Gargett, 2014)

ENDOMETRIOSIS: PATHOGENESIS

Sampson’s classification of heterotopic endometrial tissue :

1) direct or primary endometriosis [adenomyosis] 2) peritoneal or implantation endometriosis 3) transplantation endometriosis 4) metastatic endometriosis 5) developmentally misplaced endometrial tissue

ENDOMETRIOSIS: PATHOGENESIS

•  Retrograde menstruation implants (Sampson, 1927) •  Vascular migration of endometrium (Sampson,

1927) •  Metaplastic theory (Nissole, 1997) •  Defects of embryogenesis (Signorille, 2010) •  Circulating stem cells’ ectopic impl. (Gargett, 2014)

ENDOMETRIOSIS: PATHOGENESIS

•  Retrograde menstruation implants (Sampson, 1927) •  Vascular migration of endometrium (Sampson,

1927) •  Metaplastic (coelomic) theory (Nissole, 1997) •  Defects of embryogenesis (Signorille, 2010) •  Circulating stem cells’ ectopic impl. (Gargett, 2014)

ENDOMETRIOSIS: PATHOGENESIS

•  Retrograde menstruation implants (Sampson, 1927) •  Vascular migration of endometrium (Sampson,

1927) •  Metaplastic (coelomic) theory (Nissole, 1997) •  Defects of embryogenesis (Signorille, 2010) •  Circulating stem cells’ ectopic impl. (Gargett, 2014)

ENDOMETRIOSIS: PATHOGENESIS

•  Retrograde menstruation implants (Sampson, 1927) •  Vascular migration of endometrium (Sampson,

1927) •  Metaplastic (coelomic) theory (Nissole, 1997) •  Defects of embryogenesis (Signorille, 2010) •  Circulating stem cells’ ectopic impl. (Gargett, 2014)

ENDOMETRIOSIS: Prospective study

•  * designed in 2000 •  * informed, written consents for research •  * cohort : TOPs, IUFDs •  * 420 serial histological serial sections of fetal uteri •  * GA: 18-37,4w •  * 10 cases (2,4%) of adenomyosis

ENDOMETRIOSIS: Prospective study : Clinical features

K

a, b, c : EMA d, e: RO f: RP

X1,6 X 10 X 20

X 10 X 10 X 10

a, b: EMA c: SMA d: RO

ADENOMYOSIS: MZ twins

• TTTS / IUFD @ 28w • G2P1, 29 year-old

FP examination: • MCDA placenta TTTS concordant: * 1AVA (J2 J1) * unequal sharing (J1>J2) * vellamentous cord of J2 • No visceral malformations

ADENOMYOSIS: MZ twins

HES, x0,5 HES, x0,5

ADENOMYOSIS: MZ twins

HES, x0,5 HES, x0,5

ADENOMYOSIS: MZ twins

HES, x10 HES, x10

FETAL ADENOMYOSIS: Conclusion

• In our series of 420 fetal uteri: 2,4% of ectopic endometrial glands • Confirmation of previous reports (4/36 Signorille 2009; 1/13 Signorille 2010, 4/52 Signorille 2011) *Study design / understimated F of adenomyosis

• Concept of fetaly established pre-endometriotic lesions in some cases+++

• Ontogenesis hypothesis: *Aberrant epithelium-mesenchyme signaling dialogue (transition) leading to erroneus endometrial displacement during histogenesis *Aberrant migration of the Mullerian ducts : spreading of cells in the migratory pathway of fetal organogenesis across the physiological bounderies (ie neuronal over migration in CDG disorders )

FETAL ADENOMYOSIS: Conclusion

*Genetic determination of fetal adenomyosis?

• First report of identical lesions in MZ twin fetuses * Genetic control of endometriosis already suggested on twins’ studies (Hadfield et al., 1997; Kennedy et al., 1996) * high penetrance of adenomyosis/endometriosis gene(s)? • Ongoing study…

• Recent introduction of new genomic tools (NGS) will certainly enhance unravelling of adenomyosis / endometriosis puzzle in the foreseable future

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