Éditeur(s) : HAL CCSD
Résumé : Anti-Müllerian hormone (AMH) is a member of the TGF-ß superfamily. AMH is well known for its role in Müllerian duct regression in male fetuses. Postnatally, AMH is secreted by granulosa cells (GCs) of small growing follicles (preantral and small antral). However, despite the increasing interest of ovarian AMH in clinics, little is known on its mechanism of action and its role in female reproductive tract. My PhD project focuses on the identification of AMH function in the female reproductive tract.AMH signals through a type II transmembrane serine/threonine kinase receptor (AMHR-II) which forms a complex with a type I serine/threonine kinase receptor (ActR-IA, BMPR-IA, BMPR-IB). The type II receptor phosphorylates serine and threonine residues of type I receptor. Once activated, the type I receptor phosphorylates the receptor-regulated Smads (R-Smad1/5/8) which interact with a common partner Smad4. The Smad complex accumulates into the nucleus and regulates target gene expression. This canonical signalling pathway is regulated at different levels, in particular by co-receptors which amplify or antagonize TGF-ß family members action. The type I receptors and R-Smads involved in AMH effects on post-natal GCs remain unknown. In addition, to date, no co-receptor has been found for AMH. To define the involvement of the different type I receptors, we used siRNA technology to inactivate Acvr1, Bmpr1a and Bmpr1b in GC. In parallele, we analysed GC extracted from conditional mutant mice for Acvr1 and Bmpr1a. We found that BMPR-IA is the most important type I receptor for AMH to transduce its signal in GC. A Smad-Gal4/UAS-luciferase reporter gene technology allowed us to show that Smad1 and 5 are involved in AMH signaling pathway. Recently, new BMPs coreceptors were found, RGMs for Repulsive Guidance Molecules. There are three RGMs : RGMa, b and c. Because AMH shares with BMPs its type I receptors and R-Smad proteins, we hypothesized that they also share the same co-receptors, the RGM. We showed that RGMb was the only one expressed in GC and after siRNA transfection we demonstrated that this coreceptor is not essential for AMH to transduce its signal.To date, only few AMH target genes have been identified. Aromatase (Cyp19a1) and LH receptor (Lhcgr) are down-regulated by AMH in rat and porcine GCs. We used micro-array technology (Affymetrix) by comparing Wt and knockout immature ovaries to find new AMH target genes. This experiment evidenced that Ovgp1 and Kcnj2 are two new potential AMH target genes in the ovary.The last part of my project was to define a potential role of AMH in murine uterus. Only one study showed that AMHR-II is expressed in the mouse myometrium. We showed that Amh gene is slightly expressed in uterus but the results are not confirmed at the protein level. Using PCR-array, we found a lot of differentially expressed genes between Wt and Amh KO uterus. Therefore, AMH could regulate uterine function through the modulation of different genes located in the myometrium.
L’hormone anti-Müllerienne (AMH) est un membre de la famille TGF-β impliquée dans la différenciation du tractus reproductif mâle. Elle est aussi exprimée par les cellules de la granulosa de l’ovaire adulte. Cependant, son rôle physiologique chez la femelle n’a pas encore été entièrement établi. Mon projet de thèse a pour objectif d’élucider le(s) rôle(s) de l’AMH dans le tractus reproductif femelle. L’AMH transduit ses effets par l’intermédiaire de deux récepteurs transmembranaires sérine/thréonine kinase : un récepteur de type II qui lui est spécifique (AMHR-II) et un récepteur de type I (ActR-IA, BMPR-IA, BMPR-IB) qu’elle partage avec les BMPs. Après fixation de l’hormone sur le récepteur de type II, celui-ci recrute et phosphoryle le récepteur de type I. Ce dernier phosphoryle à son tour les Smads spécifiques (Smad1, 5 et 8) qui s’associent à la Smad commune, Smad4. L’ensemble transloque dans le noyau et en association avec des facteurs de transcription régule les gènes cibles de l’hormone. L'utilisation de souris KO conditionnelles pour les récepteurs Acvr1 et Bmpr1a et d'une technique de siRNA dirigés contre chacun des trois récepteurs de type I a permis de mettre en évidence que le récepteur BMPR-IA est un acteur essentiel de la voie de signalisation de l'AMH dans les cellules de la granulosa. Pour déterminer la ou les Smad(s) impliquées, une technique de gènes rapporteurs, Smad-Gal4/UAS-luciférase, a été utilisée. Nous avons pu montrer que les Smad1 et 5 sont importantes pour la transduction du signal de l'AMH dans les cellules de la granulosa. Récemment des corécepteurs aux BMPs, les Repulsive Guidance Molecule (RGMs), ont été mis en évidence. L’AMH partageant sa voie de signalisation avec les BMPs, nous avons cherché à déterminer si ces corécepteurs pouvaient également intervenir dans la voie de signalisation de l’AMH. Il existe 3 types de RGMs: RGMa, RGMb et RGMc. Nous avons montré en q-PCR que seul RGMb est exprimé dans les cellules de la granulosa alors que les 3 RGMs sont exprimés dans l’ovaire. L'utilisation de siRNA dirigés contre RGMb a permis de montrer que ce récepteur n'est pas nécessaire à la transduction du signal de l'AMH. Actuellement, seuls deux gènes cibles de l’AMH sont connus dans les cellules de la granulosa : l’aromatase et le récepteur LH. Nous avons réalisé des analyses de puces à ADN (ou micro-array) pour décrire de nouveaux gènes cibles de l'AMH. L'analyse des puces a permis de décrire de nouveaux gènes régulés par cette hormone tels qu’Ovgp1 ou Kcnj2. La dernière partie de mon projet visait à déterminer un rôle potentiel de l'AMH dans l'utérus. En effet, le récepteur de cette hormone est exprimé dans le myomètre utérin de souris permettant de supposer qu’elle peut agir sur cet organe. Nous avons pu mettre en évidence une expression faible du gène de l’Amh dans l’utérus. En revanche, l’expression et la localisation de la protéine restent encore à définir. Une expérience de PCR-array a permis de montrer que de nombreux gènes sont différentiellement exprimés entre l’utérus Wt et l’utérus KO Amh. Ceci indique que l’AMH jouerait un rôle sur la régulation de la fonction utérine qu’elle soit exprimée ou non dans cet organe.
https://tel.archives-ouvertes.fr/tel-00989662

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2014PA11T014
tel-00989662
https://tel.archives-ouvertes.fr/tel-00989662
https://tel.archives-ouvertes.fr/tel-00989662/document
https://tel.archives-ouvertes.fr/tel-00989662/file/VA_SEDES_LAURIANE_03042014.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
Aim The global increase in the rate of cesarean sections (CS) is currently an issue. We aimed to assess the rate of CS locally and to identify cases in which this procedure may have been avoidable. Methods In this prospective consecutive series, we analyzed the 478 CS carried out in our unit in 2009. We analyzed the characteristics of each case, and classified each as potentially avoidable or unavoidable. Results The total rate of CS was 24.0%, including 1.7% that was scored as potentially avoidable. Parity, gestational age at birth, birthweight, cases requiring cervical ripening, cases of labor induction, and CS during labor were all significantly higher or more frequent among potentially avoidable CS. Multivariate analysis indicated that the risk of potentially avoidable CS was positively associated with gestational age and tended to be negatively associated with parity. The main indications for potentially avoidable CS were cervical dystocia and abnormal fetal heart rate, and for unavoidable CS they were abnormal fetal heart rate and history of previous CS. Conclusion Labor, especially when induced, seems to be the key period for the prevention of ‘avoidable’ CS. This is particularly important given that potentially avoidable CS are more frequently associated with uncomplicated pregnancies than are unavoidable CS. A woman's first CS increases the likelihood of CS for subsequent deliveries, so the prevention of the first CS is a key aim for reducing the overall rate of CS
Journal of Obstetrics and Gynaecology Research

hal-01305484
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01305484
PUBMED : 27094021
DOI : 10.1111/jog.13007

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: The aim of this systematic review was to evaluate and compare the pros and cons of using living donors or brain-dead donors in uterus transplantation programs, 2 years after the first worldwide live birth after uterus transplantation. METHODS: The Medline database and the Central Cochrane Library were used to locate uterine transplantation studies carried out in human or nonhuman primates. All types of articles (case reports, original studies, meta-analyses, reviews) in English or French were considered for inclusion. RESULTS: Overall, 92 articles were screened and 44 were retained for review. Proof of concept for human uterine transplantation was demonstrated in 2014 with a living donor. Compared with a brain-dead donor strategy, a living donor strategy offers greater possibilities for planning surgery and also decreases cold ischemia time, potentially translating into a higher success rate. However, this approach poses ethical problems, given that the donor is exposed to surgery risks but does not derive any direct benefit. A brain-dead donor strategy is more acceptable from an ethical viewpoint, but its feasibility is currently unproven, potentially owing to a lack of compatible donors, and is associated with a longer cold ischemia time and a potentially higher rejection rate. CONCLUSIONS: The systematic review demonstrates that uterine transplantation is a major surgical innovation for the treatment of absolute uterine factor infertility. Living and brain-dead donor strategies are not mutually exclusive and, in view of the current scarcity of uterine grafts and the anticipated future rise in demand, both will probably be necessary.
Transplantation

hal-01447062
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01447062
DOI : 10.1097/TP.0000000000001481
PUBMED : 27607535

Éditeur(s) : HAL CCSD INVS
Résumé : National audience
Context – Cervical cancer is the second most frequent cancer of women in French Guiana. Studies have shown that populations living in remote villages in the interior of the territory have early sexual relations and that multiple sexual partnerships are frequent. Hence, the main objective of the study was to determine the prevalence of Human Papilloma Virus (HPV) in these areas.Methods – This multicentric cross sectional study was conducted in women aged 20 to 65 years, living in theremote villages along the Maroni and Oyapock rivers. Women were included on a voluntary basis after beinginformed of the study team schedule through radio address and key opinion leaders.The search for HPV and cytologic examinations were performed on each sample. HPV infection was defined bythe detection of viral DNA using the Greiner Bio One® kit. Cytologic analyses were performed using the 2001Bethesda classification.Results – Overall, 643 women were included in the study. Age-standardized HPV prevalence was 35%. Theprevalence curve by age group showed a U-shaped pattern: women over 50 years had the highest risk of being infected by HPV, followed by women aged 20-29 years. In addition, 26.1% of women with a normal smear test had HPV infection. The most frequent genotypes were HPV52, HPV58, and HPV16. On interpretable smears 1.16% of women had high grade superficial intra-epithelial (HSIL) lesions.Conclusions – The standardized prevalence of HPV in French Guiana is among the highest in the world. HSILcytological lesions were nearly 4 times more frequent than in the Île-de-France region. Given the importance of the incidence of cervical cancer in French Guiana, these results suggest it may be preferable to use HPV testing than cytology. Vaccination against HPV, preferably with the new nonavalent vaccine seems an appropriate prevention measure. However, this intervention will be a challenge to implement in this region where a significant proportion of the population is not covered by health insurance.
Contexte – Le cancer du col de l’utérus est le deuxième cancer féminin le plus fréquent en Guyane française.Des études ont montré que les populations résidant dans les communes isolées de l’intérieur du départementdébutent leur vie sexuelle de façon précoce et que le multipartenariat sexuel y est fréquent. Dans ce contexte, l’objectif principal de cette étude était de déterminer la prévalence de l’infection à papillomavirus humains (HPV) dans ces zones.Méthodes – Cette étude transversale multicentrique a été conduite auprès des femmes âgées de 20 à 65 ansrésidant dans les communes isolées des fleuves Maroni et Oyapock. Les femmes étaient incluses sur la basedu volontariat après avoir été informées du passage de l’équipe de l’étude via la radio locale et par les leadersd’opinion. La recherche d’infection à HPV et les analyses cytologiques ont été réalisées sur chaque prélèvement. L’infection à HPV était définie par la détection d’ADN viral par le kit de dépistage Greiner Bio One®. Les analyses cytologiques ont été décrites selon la classification de Bethesda 2001.Résultats – Au total, 643 femmes ont été incluses. La prévalence de l’infection à HPV, standardisée sur l’âge,était de 35%. La courbe de prévalence par classe d’âge présentait une forme en U : les femmes de plus de50 ans avaient le plus haut risque d’être infectées par HPV, suivies par les femmes âgées de 20 à 29 ans.Par ailleurs, 26,1% des femmes ayant un frottis normal étaient infectées par le HPV. Les génotypes les plusfréquents étaient HPV52, HPV58 et HPV16. Sur les frottis interprétables, 1,16% des femmes avaient des lésions de haut grade (type HSIL).Conclusions – Le taux standardisé de prévalence de l’infection par le HPV en Guyane est parmi les plus élevésau monde. Les lésions cytologiques de type HSIL étaient près de 4 fois plus fréquentes qu’en Île-de-France.Étant donné l’importance de l’incidence du cancer du col de l’utérus en Guyane, ces résultats montrent qu’il est peut être préférable d’utiliser le test HPV plutôt que la cytologie. La vaccination anti-HPV, de préférence avec le nouveau vaccin nonavalent, semble être une mesure de prévention appropriée. Pour autant, cela reste un challenge de mettre en oeuvre ces interventions dans cette région où une part importante de la population n’a pas d’assurance maladie.
ISSN: 1953-8030

Droits : info:eu-repo/semantics/OpenAccess
inserm-01407222
http://www.hal.inserm.fr/inserm-01407222
http://www.hal.inserm.fr/inserm-01407222/document
http://www.hal.inserm.fr/inserm-01407222/file/2016%2C%20Dufit%20et%20al.pdf

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Socioeconomic inequalities in cancer mortality have been observed in different European countries and the US until the end of the 1990s, with changes over time in the magnitude of these inequalities and contrasted situations between countries. The aim of this study is to estimate relative and absolute educational differences in cancer mortality in France between 1999 and 2007, and to compare these inequalities with those reported during the 1990s. METHODS: Data from a representative sample including 1% of the French population were analysed. Educational differences among people aged 30--74 were quantified with hazard ratios and relative indices of inequality (RII) computed using Cox regression models as well as mortality rate difference and population attributable fraction. RESULTS: In the period 1999--2007, large relative inequalities were found among men for total cancer and smoking and/or alcohol related cancers mortality (lung, head and neck, oesophagus). Among women, educational differences were reported for total cancer, head and neck and uterus cancer mortality. No association was found between education and breast cancer mortality. Slight educational differences in colorectal cancer mortality were observed in men and women. For most frequent cancers, no change was observed in the magnitude of relative inequalities in mortality between the 1990s and the 2000s, although the RII for lung cancer increased both in men and women. Among women, a large increase in absolute inequalities in mortality was observed for all cancers combined, lung, head and neck and colorectal cancer. In contrast, among men, absolute inequalities in mortality decreased for all smoking and/or alcohol related cancers. CONCLUSION: Although social inequalities in cancer mortality are still high among men, an encouraging trend is observed. Among women though, the situation regarding social inequalities is less favourable, mainly due to a health improvement limited to higher educated women. These inequalities may be expected to further increase in future years.
ISSN: 1471-2458

inserm-00868759
http://www.hal.inserm.fr/inserm-00868759
http://www.hal.inserm.fr/inserm-00868759/document
http://www.hal.inserm.fr/inserm-00868759/file/1471-2458-13-823.pdf
DOI : 10.1186/1471-2458-13-823

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
In intrauterine pregnancies of uncertain viability with a gestational sac without a yolk sac (with a mean of three orthogonal transvaginal ultrasound measurements <25 mm), the suspected pregnancy loss should only be confirmed after a follow-up scan at least 14 days later shows no embryo with cardiac activity (Grade C). In intrauterine pregnancies of uncertain viability with an embryo <7 mm on transvaginal ultrasound, the suspected pregnancy loss should only be confirmed after a follow-up scan at least 7 days later (Grade C). In pregnancies of unknown location after transvaginal ultrasound (i.e. not visible in the uterus), a threshold of at least 3510 IU/l for the serum human chorionic gonadotrophin assay is recommended; above that level, a viable intrauterine pregnancy can be ruled out (Grade C). Postponing conception after an early miscarriage in women who want a new pregnancy is not recommended (Grade A). A work-up for women with recurrent pregnancy loss should include the following: diabetes (Grade A), antiphospholipid syndrome (Grade A), hypothyroidism with anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies (Grade A), vitamin deficiencies (B9, B12) (Grade C), hyperhomocysteinaemia (Grade C), hyperprolactinaemia (Grade B), diminished ovarian reserve (Grade C), and a uterine malformation or an acquired uterine abnormality amenable to surgical treatment (Grade C). The treatment options recommended for women with a missed early miscarriage are vacuum aspiration (Grade A) or misoprostol (Grade B); and the treatment options recommended for women with an incomplete early miscarriage are vacuum aspiration (Grade A) or expectant management (Grade A). In the absence of both chorioamnionitis and rupture of the membranes, women with a threatened late miscarriage and an open cervix, with or without protrusion of the amniotic sac into the vagina, should receive McDonald cerclage, tocolysis with indomethacin, and antibiotics (Grade C). Among women with a threatened late miscarriage and an isolated undilated shortened cervix (<25 mm on ultrasound), cerclage is only indicated for those with a history of either late miscarriage or preterm delivery (Grade A). Among women with a threatened late miscarriage, an isolated undilated shortened cervix (<25 mm on ultrasound) and no uterine contractions, daily treatment with vaginal progesterone up to 34 weeks of gestation is recommended (Grade A). Hysteroscopic section of the septum is recommended for women with a uterine septum and a history of late miscarriage (Grade C). Correction of acquired abnormalities of the uterine cavity (e.g. polyps, myomas, synechiae) is recommended after three early or late miscarriages (Grade C). Prophylactic cerclage is recommended for women with a history of three late miscarriages or preterm deliveries (Grade B). Low-dose aspirin and low-molecular-weight heparin at a preventive dose are recommended for women with obstetric antiphospholipid syndrome (Grade A). Glycaemic levels should be controlled before conception in women with diabetes (Grade A)
ISSN: 0301-2115

hal-01295639
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01295639
DOI : 10.1016/j.ejogrb.2016.02.015
PUBMED : 27039249

Résumé : L'objectif du registre des cancers de Guyane est de collecter l ensemble des tumeurs invasives et/ou in situ survenues depuis le 1er janvier 2003 chez des patients vivant en Guyane, quels que soient la localisation de la tumeur, le lieu de diagnostic et de traitement. Cette thèse a pour but de décrire la population atteinte d un cancer afin d améliorer les connaissances sur cette maladie et ainsi de permettre aux actions de santé publique d être plus efficaces.De 2003 à 2009, le taux d incidence des cancers standardisé sur l âge était, dans les deux sexes, 30% inférieur en Guyane par rapport à la France métropolitaine et n était pas différent de celui d Amérique du Sud.Nous avons comparé l incidence, la mortalité et la survie relative des patientes atteintes d un cancer invasif du sein (CIS) et des patientes atteintes d un cancer invasif du col de l utérus (CIC) entre la Guyane et la métropole.Le ratio incidence/mortalité indiquait que les cancers du sein étaient de plus mauvais pronostic en Guyane par rapport à la métropole.La survie relative des femmes atteintes d un CIS était inférieure en Guyane par rapport à la France métropolitaine.En Guyane, le taux standardisé d incidence du cancer du col de l utérus était 4 fois plus élevé qu en métropole. Les femmes vivant dans l intérieur de la Guyane semblaient être diagnostiquées à un stade plus tardif et plus souvent sur symptômes que les femmes du littoral. L accès aux soins des migrants est un challenge et une source d inégalité de santé. La détection précoce des cancers à travers des programmes de prévention est cruciale pour améliorer la survie par cancer et notamment chez les patients étrangers.
The objective of the cancer registry of French Guiana is to compile all patients living in French Guiana with malignant invasive pathology and/or in situ lesions starting January 1st 2003 in persons living in French Guiana, whatever the tumoral location and the place of diagnosis and care. This study aimed to describe the population with invasive cancer to improve the knowledge about this disease in order to target public health interventions more effectively.The age standardised incidence rate was 30% times lower than in France in both sexes and the same than in South America.We compared incidence and relative survival of patients with invasive breast cancer (IBC) and patients with invasive cervical cancer (ICC) between women from French Guiana and metropolitan France.The ratio between incidence and mortality showed that the prognosis of IBC in French Guiana was worse than in metropolitan France.The relative survival rate among women with IBC in French Guiana was lower than among women in metropolitan France.In French Guiana, the age-standardized incidence rate of cervical cancer was four times higher than in France. Women living in remote areas seemed to be diagnosed later and more often following symptoms.Access to care for migrants is challenging and sustains health inequalities. Early detection through prevention programs is crucial for increasing cancer survival notably for foreign-born patients. Further studies with more patients and other variables could improve the knowledge about these diseases

http://www.theses.fr/2014AGUY0743/document

Éditeur(s) : HAL CCSD John Libbey Eurotext
Résumé : International audience
The principal gynaecological cancers (breast, ovary, uterus, and cervix) account for over 40% of cancers found in women worldwide. However, large differences exist, in both their incidence and geographical distribution. The French West Indies, through their location, environment, socio-economic development, lifestyle, nutrition and the origins of their populations, constitute territories with a very particular character in the heart of the Caribbean. These characteristics have an impact on public health and can affect the incidence of tumours. We report for the first time the incidence of these major gynaecological cancers in Guadeloupe. Breast, ovary and uterine cancers have lower incidences in Guadeloupe than in mainland France. By contrast, cervical cancer is more frequent in Guadeloupe than in mainland France. The mortality rates associated with breast cancer, ovary and uterine cancer are also lower in Guadeloupe than in mainland France, whereas the opposite pattern is observed for cervical cancer. These observations may be accounted for in part by a difference in the prevalence of established or suspected risk factors for each of these types of cancer.
ISSN: 0007-4551

inserm-00504624
http://www.hal.inserm.fr/inserm-00504624
DOI : 10.1684/bdc.2008.0810
PUBMED : 19258222

Éditeur(s) : HAL CCSD Ivyspring International Publisher
Résumé : International audience
Mullerian duct regression is a complex process which involves the AMH signalling pathway. We have previously demonstrated that besides AMH and its specific type II receptor (AMHRII), BMPR-IA and Smad5 are two essential factors implicated in this mechanism. Mothers against decapentaplegic homolog 4 (Smad4) is a transcription factor and the common Smad (co-Smad) involved in transforming growth factor beta (TGF-beta) signalling pathway superfamily. Since Smad4 null mutants die early during gastrulation, we have inactivated Smad4 in the Mullerian duct mesenchyme. Specific inactivation of Smad4 in the urogenital ridge leads to the partial persistence of the Mullerian duct in adult male mice. Careful examination of the urogenital tract reveals that the Mullerian duct retention is randomly distributed either on one side or both sides. Histological analysis shows a uterus-like structure, which is confirmed by the expression of estrogen receptor alpha. As previously described in a beta-catenin conditional mutant mouse model, beta-catenin contributes to Mullerian duct regression. In our mutant male embryos, it appears that beta-catenin expression is locally reduced along the urogenital ridge as compared to control mice. Moreover, the expression pattern is similar to those observed in control female mice. This study shows that reduced Smad4 expression disrupts the Wnt/beta-catenin signalling leading to the partial persistence of Mullerian duct
ISSN: 1449-2288

hal-01319890
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01319890
DOI : 10.7150/ijbs.12300
PUBMED : 27194944

Éditeur(s) : Paris : Bignoux
Siècle(s) traité(s) : 19
Droits : Domaine public
Provenance : Archives départementales de Guadeloupe
Permalien : http://www.manioc.org/patrimon/ADG17054
ADG17054