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CONVEGNO : High Tech in Endometriosi ed Infertilità Roma 04 Marzo 2009 Con LAlto Patronato del Presidente della Repubblica E con il Patrocinio della Presidenza.

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Presentation on theme: "CONVEGNO : High Tech in Endometriosi ed Infertilità Roma 04 Marzo 2009 Con LAlto Patronato del Presidente della Repubblica E con il Patrocinio della Presidenza."— Presentation transcript:

1 CONVEGNO : High Tech in Endometriosi ed Infertilità Roma 04 Marzo 2009 Con LAlto Patronato del Presidente della Repubblica E con il Patrocinio della Presidenza del Consiglio dei Ministri Patrocino del Ministero del Lavoro,della Salute e delle Politiche Sociali Patrocino del Ministero delle Pari Opportunità Patrocinio dellINPS Patrocinio dellINAIL Fondazione Italiana Endometriosi

2 High Tech in Endometriosi ed Infertilità Lettura Magistrale : Genesis of the Endometriosis Fondazione Italiana Endometriosi

3 Definition of Endometriosis ECTOPIC ENDOMETRIUM High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

4 History of Endometriosis 1690 Daniel Shroen early descriptions of what today we call endometriosis and adenomyosis. Disputatio Inauguralis Medica de Ulceribus Ulceri 1776 Roederer, Broughton, Tailford, Duff, Ludgers in the de ulceribus utero molestis observationibus descrived the desease and the simptoms 1769 Arthur Duff described the intense pain of endometriosis, and it was first seen microscopically in the late 1800s. Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

5 History of Endometriosis 1860 Carl von Rokitansky found endometrial glands in the myometrium and designated this finding as cystosarcoma adenoids uterinum. Over the following 60 years adenomyoma were considered pat hologies separate from the so-called haemorrhagic ovarian cysts (endometriosis). High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

6 History of Endometriosis 1917 Thomas Stephen Cullen researched the mucosal invasion already observed by a number of investigators in several parts of the lower abdominal cavity. Cullen clearly identified the epithelial tissue invasion as being made of uterine mucosa and defined the mechanism through which the mucosa invades the underlying tissue. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

7 History of Endometriosis 1923 J.Sampson created the term endometriosis. Dr. John Sampson was the first person to hypothesize that retrograde menstruation contributed to endometriosis 1927 High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

8 History of Endometriosis 1972 C.C.Bird The current definition of adenomyosis : Adenomyosis may be defined as the benign invasion of endometrium into the myometrium, producing a diffusely enlarged uterus which microscopically exhibits ectopic non-neoplastic, endometrial glands and stroma surrounded by the hypertrophic and hyperplastic myometrium. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

9 Theories of the Endometriosis Postulated Iatrogenic transplantation - Endometriosis is accidentally transported during surgery. Coelomic Metaplasia - This theory holds that certain cells, when stimulated, can transform themselves into a different kind of cells. The hereditary theory - Women with family members who have Endometriosis are more likely, or are susceptible to developing the disease. Liver disorders - The liver regulates and removes estrogen from the body. If the function of the liver is compromised then serious health problems can emerge, including Endometriosis. Auto-immune disorder - This disease is an autoimmune disease. Autoimmune diseases are now widely believed to occur based on genetic predisposition that may be triggered by environmental and other external factors. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

10 Theories of the Endometriosis Postulated Retrograde menstruation - this theory was postulated in the early 1927 by Dr Sampson. He speculated that during menstruation, a certain amount of menstrual fluid flowed backward from the uterus to shower the pelvic organs and pelvis lining with endometrium cells. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

11 Retrograde Menstruation Theory Postulated Present in 90% of women does not explainadenomyosis retroperitoneal extra abdominal prepuberal* post hysterectomy prostatic lack of endometriosis in all placentals mammals *An Esp Pediatr Apr;44(4):397-8 [Neonatal ovarian endometriosis. Its conservative treatment] Díez García R, Prieto Díez M, Aguilar Tremoya F. Departamento de Pediatría y Cirugía Pediátrica, Hospital General Universitario Gregorio Marañón, Madrid. Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

12 Diffusion of Endometriosis PUBMED works Endometriosis : Diffusion in the body N° Brain 2 Spinal Cord 3 Pericardium 1 Lung 95 Diaphragm 22 Leg 5 Nois and Eye 4 Lips 1 Kidney 23 Bladder 128 Liver 14 Pancresas 5 Bowel 85 Adrenals 1 Breast 1 Skin 26 Prostate 2 Total410 Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

13 Theories of the Endometriosis Proved Embriologic theory - This theory suggests that endometriosis is caused by microscopic remnants of a women's embryonic endometrial tissue (from when she was an embryo), that later develops into endometriosis. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

14 Fetal WeeksSexual Female Differentiation 0Inattivation of one chromosome X 4Initial development of Wolff ducts 5Migration of primitive germ cells 6Development of Muller ducts 9Reduction of sensivity of Muller ducts 9First meiotic profase in to the oogones 10Regression of the Wolff ducts 16First ovarian follicles 24Complete Canalizzation of the vagina 28End of moltiplication of oogones PC Sizonenko in pediatric Endocrinology,edidet J.Bertrand,R.Rappaport,and PC Sizonenko.(Baltimore:Williams e Wilkins,1993),pp Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

15 Muller ducts and Genital Tract Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

16 Internal Female Genitalia Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

17 Muller, Wolff Ducts and Gonad Fondazione Italiana Endometriosi Mesonephro cranial Mesonephro caudal Paramesonephro Gonad 7 W High Tech in Endometriosi ed Infertilità

18 Muller, Wolff Duct and Gonad Fondazione Italiana Endometriosi Mesonephro Mesonefphro Paramesonephro Gonad 7 W High Tech in Endometriosi ed Infertilità

19 Internal Genitalia Fondazione Italiana Endometriosi Tube Gonad Uterus Vagina 11 W High Tech in Endometriosi ed Infertilità

20 Embriogenetic theory is demonstrated Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

21 Uterus in mammals Bipartite ungulates (deer, moose, elk etc.), carnivores (cats, and dogs). Bicorn pigs. Simplex humans, other primates and horses. Duplex rodents (such as mice, rats and guinea pigs), marsupials and lagomorpha (rabbits and hares). Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

22 Endometriosis is related to the Tipe of Uterus Uterus Simplex endometriosis humans, other primates and horses Uterus Bipartite, Bicorn, Duplex absence of endometriosis all others placentals mammals Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

23 Septum Uterus The uterus is formed by the fusion of the two mullerian ducts. During this fusion a resorption process eliminates the partition between the two ducts to create a single cavity. This process begins caudally and advances cranially, thus a complete septum formation represents an earlier disturbance of this absorption than the incomplete form. Causes for incomplete absorption are not known. Heinonen PK (March 2006). "Complete septate uterus with longitudinal vaginal septum". Fertil. Steril. 85 (3): 700–5. Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

24 Human Uterine Malformations Prevalence general population 6,7%, infertility population 7,3%, recurrent miscarriages 16% Sotirios H. Saravelos, Karen A. Cocksedge and Tin-Chiu Li. "Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal.". Human Reproduction Update, Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

25 Is there an association between septate uterus and endometriosis? Septate uterus (n = 120) Endometriosis (%) 31 (25.8) Controls (n = 486) Endometriosis (%) 74 (15.2) Human Reproduction Vol.21, No.2 pp. 542–544, 2006 Is there an association between septate uterus and endometriosis? Frank Nawroth1,3, Gohar Rahimi2, Claudia Nawroth2, Dolores Foth2, Michael Ludwig1 and Torsten Schmidt2 1Endokrinologikum Hamburg, Centre for Hormone and Metabolic Diseases, Reproductive Medicine and Gynaecological Endocrinology, and 2Department of Obstetrics and Gynaecology, University of Cologne, Germany High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

26 Mullerianosis Uterus-like mass of müllerian origin in the lumbosacral region causing cord tethering. Report of two cases. Sharma MC, Sarkar C, Jain D, Suri V, Garg A, Vaishya S. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. Fertil Steril Oct;84(4):1017. Accessory uterine appendage may be a new Müllerian malformation. Umobi MA, Meltz RC, Barmat LI. Department of Obstetrics and Gynecology, Crozer-Chester Medical Center, Upland, Pennsylvania 19013, USA. Hum Pathol Aug;36(8): Intra-abdominal ovarian-type mucinous cystadenoma associated with fallopian tube-like structure and aberrant epididymal tissue in a male patient. Rizzardi C, Brollo A, Thomann B, Santirocco C, Melato M. Unit of Pathology of the University of Trieste, Ospedale Maggiore, I Trieste, Italy. Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

27 Embriologic theory Proved Explains adenomyosis retroperitoneal extra abdominal prepuberal post hysterectomy prostatic endometriosis only in mammals with simplex uterus Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

28 High Tech in Endometriosi ed Infertilità Development of the uterus Initial stratification of the uterine wall occurred at 14 WG. At this age, the endometrial epithelium was simple columnar to pseudostratified and consisted of microvillous cells. At WG the endometrial epithelium became clearly pseudostratified, with active ciliogenesis and a predominance of microvillous cells. Primordia of tubular glands were present at 20 WG. Microvillous cells still predominated in the endometrial epithelium at WG and showed morphological features of apoptosis. The endometrial stroma at this stage was organizing into a thick lamina propria provided with subepithelial capillary plexuses. Our data showed that the epithelial differentiation and distribution in the uterus occur in the human fetus in a similar way as in the adult. Archives of Histology and Cytology Vol. 70 (2007), No. 1 p Ultrastructural dynamics of the human endometrium from 14 to 22 weeks of gestation Fabrizio Barberini 1), Sayoko Makabe 2), Gianfranco Franchitto 1), Silvia Correr 1), Michela Relucenti 1), Rosemarie Heyn 1) and Giuseppe Familiari 1) 1) Department of Anatomy, University of Rome La Sapienza 2) Department of Obstetrics and Gynaecology, Toho University Fondazione Italiana Endometriosi

29 Demonstration of embriogenetic Theory n press ECTOPIC ENDOMETRIUM IN HUMAN FETUSES IS A COMMON EVENT AND SUSTAINS THE THEORY OF MULLERIANOSIS IN THE PATHOGENESIS OF ENDOMETRIOSIS Pietro G. Signorile1*, Feliciano Baldi2, Rossana Bussani3, Mariarosaria DArmiento4, Maria De Falco5, Alfonso Baldi1,2* 1 Fondazione Italiana Endometriosi, Rome, Italy; 2 Dept Biochemistry, Sect Pathology, Second University of Naples, Naples, Italy; 3 Dept. of Pathology, University of Trieste, Trieste, Italy; 4 Dept. Scienze Biomorfologiche, University of Naples "Federico II", Naples, Italy. 5 Dept Evolutive and Comparative Biology, University of Naples "Federico II", Naples, Italy. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

30 Demonstration of embriogenetic Theory We speculated that, if the basis of endometriosis is an alteration during organogenesis, it would be possible to see ectopic endometrial tissue dislocated outside the uterine cavity of human female fetuses. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

31 Fetuses Enrolled N° Gestational age Cause of death Presence of ectopic endometrium 5 23 weeks Placental pathology No 6 15 weeks Voluntary abortion No 7 20 weeks Voluntary abortion No 8 newborn Primary atypical pneumonia No 9 newborn Acute interstitial pneumonitis No weeks Voluntary abortion No weeks Placental pathology No weeks Placental pathology No weeks Voluntary abortion No weeks Voluntary abortion No weeks Voluntary abortion No weeks Voluntary abortion No weeks Voluntary abortion No weeks Voluntary abortion No weeks Placental pathology No weeks Placental pathology No 21 newborn Acute interstitial pneumonitis No 22 newborn Primary atypical pneumonia No weeks Voluntary abortion No weeks Voluntary abortion No 25 newborn Cardiac malformation No 26 newborn Cardiac malformation No weeks Voluntary abortion No weeks Placental pathology No weeks Voluntary abortion No 30 newborn Cardiac malformation No 31 newborn Cardiac malformation No weeks Voluntary abortion No 33 newborn Acute interstitial pneumonitis No weeks Voluntary abortion No 35 newborn Cardiac malformation No weeks Placental pathology No 1 18 weeks Voluntary abortion Yes 2 24 weeks Placental pathology Yes 3 25 weeks Placental pathology Yes 4 16 weeks Voluntary abortion Yes Yes : Ectopic Endometrium High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

32 Methods Pelvic organs were collected en-block, fixed in paraphormaldeyde and included in paraffin. We performed histological analysis of the pelvic organs for each fetus, using Hematoxylin/Eosin and Hematoxylin/Van Gieson staining. For immunohistochemistry 5-7 μm specimen sections embedded in paraffin, were cut, mounted on glass and dried overnight at 37°C. All sections were then deparaffinized in xylene, rehydrated through a graded alcohol series and washed in phosphate-buffered saline (PBS). PBS was used for all subsequent washes and for antiserum dilution. Tissue sections were quenched sequentially in 3% hydrogen peroxide in aqueous solution and blocked with PBS-6% non-fat dry milk (Biorad, Hercules, CA, U.S.A.) for 1 h at room temperature. Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

33 Methods Slides were then incubated at 4°C overnight at 1:100 dilution with the following antibodies: the affinity-purified rabbit antibody ERα for the estrogen receptor (Santa Cruz, Santa Cruz, CA, USA; cat. # sc-542) and the mouse monoclonal antibody M11 for CA125( Dako Laboratories, Carpinteria, CA, USA). After three washes in PBS to remove the excess of antiserum, the slides were incubated with diluted goat anti-rabbit or anti-mouse biotinylated antibodies (Vector Laboratories, Burlingame, CA, U.S.A.) at 1:200 dilution in PBS-3% non-fat dry milk (Biorad) for 1 h. All the slides were then processed by the ABC method (Vector Laboratories) for 30 min at room temperature. Diaminobenzidine (Vector Laboratories) was used as the final chromogen and hematoxylin was used as the nuclear counterstain. Negative controls for each tissue section were prepared by leaving out the primary antiserum. Positive controls constituted of tumor tissues expressing either the estrogen receptor or CA125, were run at the same time. All samples were processed under the same conditions. Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

34 Ectopic Endometrium Prevalence in Fetuses Fetuses* 11% Adult10%-15% * First observation Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

35 Distribution of Ectopic Endometrium in the Fetus Case 125 weeks fetus Ectopic endometrial structure in the deep recto-vaginal septum, near perineal floor. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

36 Distribution of Ectopic Endometrium in the Fetus High Tech in Endometriosi ed Infertilità

37 Distribution of Ectopic Endometrium in the Fetus Case 224 weeks fetus Ectopic endometrial structure in the proximity of the Douglas pouch. High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

38 Distribution of Ectopic Endometrium in the Fetus Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

39 Distribution of Ectopic Endometrium in the Fetus Case 318 weeks fetus Ectopic endometrial structure in the rectal tube at the level of muscularis propria High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi

40 Distribution of Ectopic Endometrium in the Fetus Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

41 Distribution of Ectopic Endometrium in the Fetus Case 416 weeks fetus Ectopic endometrial structure in the mesenchimal tissue close to the posterior wall of the uterus. Ectopic endometrial structure in the miometrium, primitive nest of adenomyosis Fondazione Italiana Endometriosi High Tech in Endometriosi ed Infertilità

42 Distribution of Ectopic Endometrium in the Fetus Fondazione Italiana Endometriosi u bl re D D * High Tech in Endometriosi ed Infertilità

43 Conclusion Past Origin Endometriosis unknown (chronic desease) PresentEmbriogenetic minimal defect at the origin of the Endometriosis (congenital disease) FutureTo define the molecular and organogenetic misprogramming events causing the minimal defects in uterus To develop new strategies for prevention, diagnosis and therapy Fondazione Italiana Endometriosi

44 SI RINGRAZIANO Il Presidente della Repubblica Italiana Giorgio Napolitano per lAlto Patronato La Presidenza del Consiglio dei Ministri per il Patrocinio Il Ministero del Lavoro, della Salute e delle Politiche Sociali per Il Patrocinio Il Ministero delle Pari Opportunità per il Patrocinio Gli Enti INPS ed INAIL per il Patrocinio Le Donne iscritte allAssociazione Italiana Endometriosi Lo staff dellAssociazione Italiana Endometriosi e della Fondazione Italiana Endometriosi Lo staff medico e di ricerca Le Università : Federico II e II Università di Napoli, Università di Trieste ed il CNR di Napoli La EVENTI MADE IN ITALY Il Rome American Hospital UN RINGRAZIAMENTO PARTICOLARE A : Roberta Riposati, Angela Ricci, Sara Alessandrini che con dedizione aiutano le donne High Tech in Endometriosi ed Infertilità Fondazione Italiana Endometriosi


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