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A commonly prescribed contraceptive, the synthetic progestin norethindrone (NET) inhibits ovulation in humans. However, ecotoxicological data are lacking. Preliminary tests produced an LC50 for NET of > 1.0 mg/L (96-hour, fathead minnow (FHM) and medaka) and a NOEC of 242.0 µg/L, a LOEC of 485.0 µg/L (7-day, growth for FHM and medaka). Reproductive testing revealed a LOEC for fecundity of 24.1 ng/L (21 days, medaka). Further testing confirmed the LOEC of 24.1 ng/L while defining a NOEC of 4.7 ng/L (28 days, medaka). Effect of NET in medaka life-cycle exposure at concentrations exceeding 4.7 ng/L was evident. Few females were present in the 24.7 ng/L exposure concentration, with none in the 104.6 ng/L. Egg production was significantly reduced at concentrations exceeding 4.7 ng/L. Additionally, weight, condition factor and somatic indices were significantly different in males exposed to concentrations exceeding 4.7 ng/L. For fecundity and sexual differentiation; the NOEC was 4.7 ng/L, the LOEC 24.6 ng/L; growth and somatic indices, the NOEC was more appropriately 0.9 ng/L, with effect evident at 4.7 ng/L. Sexual differentiation of the F1 population was similar to the F0. A defining result of this test was development of exceptionally large ovaries in NET- exposed female medaka, perhaps indicative of a threshold limit for exposure in these fish. Results of FHM life-cycle testing were similar, establishing a NOEC for fecundity of 0.9 ng/L, a LOEC of 4.8 ng/L. NET's inhibitory effect on gonadal development was obvious; GSI NOEC for males, 4.8 ng/L, and histological examination confirmed the presence of intersex development at elevated concentrations. Normal physical development and growth were impaired, generally at concentrations exceeding 24.1 ng/L. At exposure concentrations exceeding 4.8 ng/L, external sexual confirmation of fish was difficult; LOEC for finspot development in females, 4.8 ng/L. Sexual determination of the 97.1 ng/L exposure group was impossible; externally, all fish appeared male and internal examination revealed no gonadal development.

Progestins are synthetic progestogens that prevent pregnancy by thickening the mucous of the cervix to prevent sperm entry and by disrupting implantation via alteration of the timing of endometrial changes occurring during a normal menstrual cycle. Various hormonal birth control methods utilize progestins, with some of the most effective types of birth control methods being long-acting reversible contraceptives. These include hormonal injections such as depot medroxyprogesterone acetate (DMPA), hormonal implants such as Nexplanon, and hormone-releasing intrauterine devices (IUDs) such as Mirena. Although there have been many studies on the safety and effectiveness of these methods, fewer studies have examined how these hormonal methods may impact the bacterial environment of the vagina, better known as the vaginal microbiome. The health of the vagina relies heavily on the bacteria composing the microbiome. Changes in species composition correlate with higher risk of sexually transmitted infections (STIs) and adverse pregnancy outcomes. When women select their preferred hormonal contraceptive method, they should know if it will impact their vaginal microbiome and increase susceptibility to disease. Twenty-one patients enrolled in this study, with one patient initiating DMPA, 14 initiating levonorgestrel (LNG) IUD, and 6 initiating the etonogestrel subdermal implant (ESI). At initiation, 3 months post initiation, and 6 months post initiation, no differences were seen in the vaginal microbiomes of each of the women enrolled in the study. Some differences in the vaginal microbiota of postpartum women and those who were not postpartum were seen. More specifically, enrichment of three families, Lachnospiraceae, Ruminococcaceae, and Erysipelotrichaceae, was seen in women who were more than 12 weeks postpartum, but the effects of those differences remain unclear. Although our sample size was small, the lack of changes in the vaginal microbiome in women initiating long-acting progestin contraception is reassuring; further study in this area is needed.

The objective of this experiment was to examine the effects of varying the interval from follicular wave emergence to progestin removal on follicular dynamics and the synchrony of estrus. The experimental design was a 2x2x2 factorial with GnRH or estradiol-17 beta (E2) + progesterone (P4), controlled internal drug-releasing device (CIDR) treatment duration, and PG or saline treatment as main effects. Cycling, Angus cows (n=49), on d 6 to 8 of the estrous cycle, were randomly assigned to receive a CIDR treatment for 7 or 9 d. Approximately half of the cows from each CIDR group received either GnRH (100 mcg) or E2+P4 (1 mg E2 + 100 mg P4) at CIDR insertion. Cows in GnRH or E2+P4 groups were further divided into those that received PG (37.5 mg) or saline at CIDR insertion. All cows received PG (25 mg) 1 d prior to CIDR removal. The interval from follicular wave emergence to CIDR removal was longer for cows treated with GnRH (6.6 d) or a CIDR for 9 d (6.5 d) compared to those treated with E2+P4 (4.7 d) or a 7-d CIDR (4.8 d) (P < 0.05). Cows treated with PG or GnRH at CIDR insertion or a 9-d CIDR had a larger dominant follicle (DF) at CIDR removal than those treated with saline, E2+P4, or a 7-d CIDR. (P < 0.07). Altering the interval from wave emergence to progestin removal created differences in size of the DF at CIDR removal but did not affect the synchrony of estrus. / Master of Science

Orientador: José Maurício Barbanti Duarte / Banca: Pietro Sampaio Baruselli / Banca: Marcelo Alcindo de Barros Vaz Guimarães / Banca: Ciro Moraes Barros / Banca: Paulo Henrique Franceschini / Resumo: O conhecimento das técnicas de reprodução assistida nas espécies selvagens pode ser importante para futuros programas de conservação in situ e ex situ. Nosso objetivo foi estabelecer um protocolo de superovulação para o veado-catingueiro (Mazama gouazoubira). Para tanto, foram realizados dois experimentos: (1) No ano de 2007, seis fêmeas da espécie M. gouazoubira receberam um dispositivo intravaginal de progesterona (CIDR®) por 8 dias seguido por uma aplicação i.m. de 0,5mg de BE no momento da inserção (D-8) e de 265μg de cloprostenol (PGF2α) no momento da retirada (D0). Posteriormente foram divididas em três grupos (n=2): no primeiro os animais receberam 600UI de eCG (Tratamento A), no segundo 300UI de eCG (Tratamento B) e no terceiro 250UI de FSH+PVP. (Tratamento C), todos administrados no dia 4 (D-4). O segundo experimento (2) foi desenvolvido no ano de 2009 e utilizou outras seis fêmeas da mesma espécie, divididas em dois grupos (n=3): o primeiro recebeu CIDR® por 8 dias, seguido por uma aplicação i.m. de 0,25mg de BE no D-8, 700UI eCG no D-4 e 265μg PGF2α no D0 (Tratamento D) e o segundo recebeu CIDR® por 7,5 dias seguido por uma aplicação i.m. de 0,25mg de BE no D-7,5; 130mg de FSH em oito doses iguais (iniciando em D-3 e finalizando em D-0,5) e 265μg de PGF2α no D0 (Tratamento E). Em cada experimento os tratamentos foram delineados no esquema "cross-over", com um intervalo de 44 dias após a remoção do CIDR®. Todas as fêmeas receberam uma aplicação i.m. de PGF2α 14 dias após a retirada do CIDR®. Um macho fértil foi utilizado para a detecção do estro e fertilização. A eficácia dos Tratamentos foi avaliada pelo comportamento reprodutivo, contagem de CLs e folículos (maiores que 3mm) e colheita de embriões por laparoscopia, sete dias após a primeira cópula. No Experimento 1, ainda... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Knowledge of assisted reproduction techniques for wild animals is useful for future in situ and ex situ conservation programs. The present study aimed to establish a superovulation protocol for brown brocket deer (Mazama gouazoubira) by evaluating the ovulation rate, the presence of functional corpora lutea (CL), the number of embryos and their development stages after superovulation using different treatments. For this, two experiments were realized: (1) in 2007, six female Mazama gouazoubira received an intravaginal device (CIDR) for 8 days, followed by 0.5mg i.m. injection of OB at the time of insertion (D-8) and 265μg of cloprostenol (PGF2α) at the time of removal (D0). Next, the hinds were divided into 3 groups (n=2): group 1 received an i.m. injection of 600IU eCG (Treatment A), group 2 300IU of eCG (Treatment B) and group 3 250IU of FSH+PVP (Treatment C), all on D4 (D-4). The second Experiment (2) was developed in 2009 and also used six hinds from the same species divided into 2 groups (n=3): the first received CIDR for 8 days, followed by 0.25mg i.m. injection of OB on D-8, 700IU of eCG on D-4 and 265μg of PGF2α on D0 (Treatment D) and the second received CIDR for 7.5 days followed by 0.25mg i.m. injection of OB on D-7.5, 130mg of FSH divided into eight equal doses [beginning on D-3 and ending D-0.5] and 265μg of PGF2α on D0 (Treatment E). In each experiment, the treatments were „crossed over‟ with 44 day intervals after CIDR removal. All the hinds received an i.m. injection of PGF2α 14 days after CIDR® removal. A fertile male was used for estrus detection and fertilization. Treatment efficacy was evaluated by reproductive behavior, observation of CL, unruptured follicles (over 3mm) and embryo collection via laparoscopy 7 days after the first copulation. In Experiment 1, feces were collected... (Complete abstract click electronic access below) / Doutor

Les patients atteints de syndromes d’hypoventilation centrale ont une hypoventilation associée à une sensibilité au CO2 réduite ou abolie, au moins pendant le sommeil. A ce jour, il n’existe pas de traitement pharmacologique (Gozal, 1998, Cielo & Marcus, 2014). Ce constat nous a conduit à étudier les mécanismes de modulation de la commande centrale respiratoire (CCR) de base ou lors d’une hypercapnie par 3 molécules distinctes (i.e. l’étonogestrel, l’érythropoïétine, la leptine) dontl’implication dans la réponse ventilatoire à l’hypercapnie préalablement démontrée ou suggérée a éveillé un intérêt thérapeutique.Dans ce contexte, l’objectif de ces travaux de thèse a constitué d’une part à caractériser l’influence de ces molécules sur la ventilation de base et sur la réponse ventilatoire à l’hypercapnie,d’autre part à déterminer en parallèle leurs mécanismes d’action. Pour aborder cette problématique,nous avons mené nos expérimentations sur des souris sauvages recevant de l’étonogestrel et des souris génétiquement modifiées sous-exprimant l’érythropoïétine (Epo-TAgh) et déficientes en leptine(ob/ob). Afin appréhender les mécanismes centraux mis en jeu par l’ETO en normocapnie, nous avons couplé l’analyse de la CCR lors d’applications pharmacologiques à de l’histologie fonctionnelle sur des préparations ex vivo de bulbe rachidien-moelle épinière isolé de souris nouveau-née. En revanche pour étudier les mécanismes d’actions de l’Epo et la leptine en normocapnie et lors d’une hypercapnie,nous avons couplé une analyse des variables ventilatoires enregistrées par pléthysmographie à de l’histologie fonctionnelle sur des souris ob/ob et Epo-TAgh. Pour ces dernières, une analyse de la CCR sur des préparations ex vivo de bulbe rachidien-moelle épinière isolé de souris nouveau-né Epo-TAgha également été réalisée. Nos données obtenues chez l’animal sauvage sont permis de mettre en évidence un effet dose dépendant de l’ETO sur la fR de base en normocapnie. L’effet global du progestatif semble résulter de la sommation d’un effet facilitateur bulbaire dépendant d’interactions avec des récepteurs GABAA etNMDA et de l’activation des systèmes sérotoninergiques. L’ensemble de nos expériences réalisées sur les souris génétiquement modifiées Epo-TAgh et ob/ob ont permis de conclure que l’Epo ou la leptine n’était pas nécessaire à l’obtention d’une réponse ventilatoire à l’hypercapnie mais qu’un déficit en Epo ou en leptine induisait une modification du patron ventilatoire et du réseau neuronal activé par l’hypercapnie au niveau bulbaire pour l’Epo et également supra-bulbaire et diencéphalique pour la leptine. Nous posons ainsi l’hypothèse que ces modifications soient reliées à une plasticité neuronale importante induite par la déficience en Epo et en leptine. Les données obtenues ouvrent des perspectives quant au fait de déterminer si les mécanismes enclenchés par les progestatifs de la famille des gonanes visant à moduler la CCR pourraient être utilisés comme une alternative thérapeutique pertinente pour le traitement des troubles respiratoires rencontrés chez des patients souffrants de syndrome d’hypoventilation centrale. Enfin, la plasticité du réseau neuronal respiratoire induite par la déficience en Epo et en leptine pourrait aider à comprendre plus encore les mécanismes de la chémoréception centrale au CO2/H+ et mettre en avant des cibles thérapeutiques potentielles jusque-là insoupçonnées pour le traitement des CHS. / Non communiqué

Current epidemiological data showing that the use of the injectable contraceptive progestin Depotmedroxyprogesterone acetate (DMPA) is associated with increased HIV-1 acquisition is controversial. However, animal and ex vivo data reveal plausible biological mechanisms whereby MPA may increase HIV-1 acquisition. Relatively high levels of endogenous progesterone (P4) found in the luteal phase of the menstrual cycle have also been linked to increased HIV-1 acquisition in animal, clinical and ex vivo models. One of the central hypotheses of the present study was that the mechanism of MPA-induced increase in HIV-1 infection occurs via a different mechanism to that of the luteal phase. Furthermore, MPA has been shown to activate both the glucocorticoid receptor (GR) and its target, the progesterone receptor (PR) isoform B (PR-B), which are both transcription factors and regulate genes involved in immune function. Both the GR and PR are expressed in the cervix, the primary site of heterosexual HIV-1 infection. PR is regulated by endogenous estrogen (E2), of which the concentrations fluctuate throughout the menstrual cycle, and GR expression also varies in response to stress hormones, leading to conditions of varied relative levels of GR/PR. The immune-related consequences of changing the relative levels of GR and PR-B are not well understood. Therefore another hypothesis of this study was that changing the relative levels of GR/PR-B modulates HIV-1 infection and immunomodulatory gene expression in response to the GR/PR agonist, MPA. Since GR and PR-B recognize similar DNA target sequences and may regulate the same genes at the same time, the final hypothesis of the present study was that GR and PR-B reciprocally modulate each other’s activity, through possible association. To investigate the effects of exogenous hormones on HIV-1 infection and mechanisms thereof, peripheral blood mononuclear cells (PBMCs) and TZM-bl cervical cells were used as model systems for HIV-1 infection. These cells were stimulated with P4 and E2 at concentrations mimicking the menstrual cycle phases or with levels of MPA at the upper range of peak serum levels detected in DMPA users. Cells were infected with the R-tropic HIV-1 infectious molecular clone, HIV-1Bal_Renilla and luciferase assays were used to measure HIV-1 infection. Levels of HIV-1 CD4 receptor and CCR5 co-receptor protein or mRNA were measured by flow cytometry or qPCR, respectively, while activation of CD4+ T cells using the activation marker CD69 was measured by flow cytometry in PBMCs. To investigate the effects of changing GR/PR-B levels on HIV-1 infection and immune gene regulation, GR/PR levels were altered in End1/E6E7 immortalized endocervical and HeLa/TZM-bl cervical carcinoma cells by GR siRNA knockdown with or without the simultaneous over-expression of PR-B, and cells were stimulated with MPA or the GR agonist Dexamethasone. mRNA expression iii of key immunomodulatory genes in End1/E6E7 and HeLa cells was measured by qPCR. The modulation of GR activity by PR-B was assessed by promoter-reporter assay in COS1 and U2OS cells over-expressing GR and PR and stimulated with GR- and/or PR-specific ligands. Association of GR and PR-B was measured by co-immunoprecipitation in COS1 and MCF-7 cells, while co-localization of GR and PR-B was measured by confocal microscopy and super-resolution structured illumination microscopy in COS1 cells. MPA significantly increased HIV-1 infection in both PBMCs and TZM-bl cells, while luteal phase hormones did so to a lesser extent. However, MPA but not luteal phase hormones increased the ratio of CD4+/CD8+ T cells in PBMCs. MPA but not luteal phase hormones also increased CCR5 protein expression on CD4+ T cells in PBMCs and total CCR5 mRNA expression in TZM-bl cells. In addition, MPA but not luteal phase hormones increased activation of CD4+ T cells in PBMCs. Using a GR antagonist or GR siRNA, it was shown that the GR but not PR-B is required for MPA-, but not luteal phase hormone-induced increased HIV-1 infection in PBMCs and TZM-bls. The presence of PR-B altered the anti-inflammatory, GR-mediated regulation of some key immunomodulatory genes, including GILZ and IL-6, in End1/E6E7 and HeLa cells in response to MPA. In general, basal (unliganded) expression of immunomodulatory genes exhibited a pro-inflammatory profile in the presence of PR-B. Co-immunoprecipitation assays showed that GR and PR-B appeared to associate. Confocal microscopy suggested GR and PR co-localized in the nucleus in response to GR- and/or PRspecific ligands, while super-resolution microscopy showed that co-localization occurred in select regions within the nucleus. Taken together, MPA increases HIV-1 infection in a manner different from that of luteal phase hormones, most likely involving increased CD4+ T cell frequency (CD4+/CD8+ ratio), activation and increased expression of CCR5 on CD4+ T cells, and requiring the GR. Furthermore, PR-B modulates GR-mediated immune function gene regulation, via potential association and region-specific nuclear co-localization. This suggests that the relative levels of GR/PR may play an important role in determining the inflammatory and immune responses and HIV-1 infection in HIV-1 target cells, both in DMPA users and women not using hormonal contraception.

The uterine endometrium undergoes cyclical phases of cell proliferation, cell differentiation, and menstruation under the influence of the ovarian hormones, estrogen and progesterone. Since the data necessary to create a classical kinetic model of these signaling pathways is lacking, we used a Boolean network approach that includes the influences of various growth factors and the differential expression of their receptors under the influence of estrogen and progesterone. Results show a gain in endometrial tissue and loss of tissue during menstruation that mirrors what can be expected over the course of a normal menstrual cycle in women, where the endometrium typically reaches a thickness of approximately 10 mm. We utilized an existing model of the normal menstrual cycle that was used to predict hormonal changes following administration of GnRH analogues. We adapted this model to provide the hormonal and ovarian compartments that would interact with our model of the endometrial cycle.

Background: Recent studies are changing the way physicians and patients view hormone replacement therapy (HRT). This study was performed at the East Tennessee State University (ETSU) internal medicine clinic to evaluate the current behaviors of university physicians and patients with respect to HRT. Methods: A retrospective chart review was conducted at the main internal medicine outpatient clinic at ETSU. Two hundred seventy-four postmenopausal female patients were randomly selected using a computerized systematic sampling technique of International Classification of Diseases, Ninth Revision (ICD-9) codes for menopause or postmenopause. The study period was from July 2002 until June 2004. Patients were postmenopausal women age 35 years or over who had been seen by their physicians at least twice a year during the study period. Patients who were noncompliant with HRT or physician's visits or had contraindications or side effects to HRT mandating discontinuation of the treatment were excluded. Data regarding physicians' patterns in discussion and discontinuation of the therapy and patients' responses were collected. Epi Info 2002 was used for statistical analysis. Results: One hundred seventy-seven patients met all of the criteria, of whom 140 were 35 to 75 years of age. Of this age group, 49 patients (35%) had coronary artery disease (CAD), 101 (72.1%) were on HRT prior to July 2002, and 30 (21.4%) had osteoporosis. Seventy-five patients (53.6%) had documented discussions with their physicians about HRT after July 2002. Most patients who were on HRT had no CAD (p = .0008). Of the patients who were on HRT, only 36 (35.6%) continued treatments (23 continued the same dose, and 13 had the dose modified), whereas 65 (64.3%) had treatments discontinued. HRT discussions were carried on mostly when patients had treatments stopped or modified (p = .0032). Of these patients who had discussions, 60 (80%) were advised to stop or modify the dose and agreed, and only 15 (20%) disagreed or received unbiased discussions from their physicians about HRT. Thiry-seven patients were over 75 years of age. This older group had a higher rate of HRT discontinuation (82%) but a lower rate of documented discussion (22%) than the younger group. Conclusion: Physicians should pay more attention to the importance of providing high-quality and well-balanced patient counseling when addressing uncertain treatments and adequately document discussions with patients in medical records.

ABSTRACT Selective progesterone receptor modulators (SPRM) represent a new class of synthetic steroids which can interact with the progesterone receptor (PR) and can exert agonist, antagonist or mixed effects on various progesterone target tissues in vivo. VA-2914 is a selective progesterone receptor modulator with potential contraceptive activity. We evaluated VA 2914 for ovulation inhibition in women, using three experimental doses ( 2,5 mg/d, 5 mg/d, 10 mg/d ) given continuously for three months. We examined the endometrial impact in each group. Anovulation (defined by absence of progesterone above 3 ng/ml ) was obtained in nearly 80% women in the 5 and 10 mg/d groups with a great rate of amenorrhea ( 81.2 and 90% cases in the 5 and 10 mg/d groups ). Estradiol levels remained in the physiological follicular phase range. Endometrial histological analysis show predominantly usual patterns of secretory phase. Some cystic glandular dilatations are observed in rare cases ; any hyperplasia was detected. VA-2914 induces amenorrhea while progestins cause endometrial spotting and bleeding. This abnormal bleeding due to progestins is a consequence of focal stromal proteolysis by increase in naked vessel size and density. We quantified the effects of VA 2914 on endometrial vascularisation, fibrillar matrix and VEGF-A expression in endometrial biopsies from 41 women before and after 12 weeks daily treatment (2,5 , 5 or 10 mg/d VA 2914 versus placebo). We did not observed changes in endometrial vessels, collagen network and VEGF-A distribution between the luteal phase at baseline and under VA 2914. From these observations, we can assess that VA 2914 does not behave like a progestin since it does not alter the endometrial matrix nor the pattern of endometrial vessels. Résumé : Les modulateurs sélectifs du récepteur de la progestérone ( SPRMs) constituent une nouvelle famille de stéroïdes présentant des propriétés mixtes agonistes ou antagonistes en fonction des gènes cibles, du contexte cellulaire, de la présence simultanée dautres ligands du récepteur de la progestérone (Spitz 2003). Le chef de file de cette famille, la mifépristone, est utilisé depuis plusieurs décennies pour ses propriétés abortives. Son intérêt dans la contraception post coïtale a été démontré. Des molécules aux propriétés abortives réduites sont à létude ou en cours de développement dans les domaines de la contraception, du cancer du sein, du traitement médical de lendométriose et des fibromes utérins (Pintiaux et al. 2009). Le VA2914 que nous étudions, fait partie de ces SPRMs en cours de développement. Nous avons démontré sa capacité à inhiber lovulation à partir de 5 mg administrés par voie orale quotidiennement. Il exerce une action endométriale participant vraisemblablement à leffet contraceptif . Il ninhibe pas le développement folliculaire et permet déviter la carence estrogénique observée sous progestatif antigonadotrope. A partir de la dose de 5 mg par jour, son utilisation saccompagne dun haut taux daménorrhée (Chabbert-Buffet et al. 2007). Lutilisation dun SPRM au long cours pose le problème dun endomètre soumis aux estrogènes endogènes sans opposition progestative. Limpact dun SPRM sur lendomètre varie en fonction de la molécule, de son dosage, de la présence concomitante dautres stéroïdes et de lespèce à laquelle ce SPRM est administré (Chwalisz et al. 2000). Des aspects histologiques particuliers sont décrits dans les endomètres soumis aux SPRMs. Il sagit de la coexistence daspects histologiques non présents de façon simultanée physiologiquement ( aspects sécrétoires et prolifératifs coexistant au sein du même endomètre, signes dapoptose et dactivité mitotique au sein dune même glande) (Mutter et al. 2008). La persistance dune activité mitotique est observée dans les glandes endométriales des patientes anovulatoires soumises au VA2914 (Chabbert-Buffet et al. 2007). Lutilisation de cette molécule quotidiennement et à long terme nest donc pas dactualité contrairement à son utilisation ponctuelle dans le cadre de la contraception postcoïtale (Creinin 2006). La place des SPRMs en contraception classique doit être définie. Différents schémas dadministration et différents dosages devront être évalués en termes defficacité et de sécurité. Lutilisation des SPRMs pourrait être utile pour contrer les saignements indésirables observés lors de la prise de progestatif seul. Contrairement aux patientes soumises aux progestatifs seuls, les patientes sous VA2914 présentent un haut taux d'aménorrhée. Lors du saignement physiologique menstruel comme lors de l'administration de progestatif seul, la dégradation locale du stroma endométrial et une lyse du réseau fibrillaire riche en collagène sont classiquement observées (Galant et al. 2000). Sous VA2914, nous nobservons pas de dégradation de la matrice extracellulaire (Ravet et al. 2009). Le rôle des métalloprotéases matricielles dans les saignements normaux et pathologiques de l'endomètre humain est bien connu . Le profil d'expression des métalloprotéases matricielles dans l'endomètre des patientes traitées par VA2914 à différents dosages peut contribuer à lintégrité endométriale observée. Une angiogenèse aberrante est observée sous progestatif. Une modification de la densité vasculaire endométriale et une altération de la maturation de la paroi des vaisseaux, déficitaire en péricytes et en cellules musculaires lisses ont été décrites (Hickey et al. 1999; Hickey et al. 2000; Jondet et al. 2005; Rogers et al. 1993; Stephanie et al. 2007). L'observation de la vascularisation de lendomètre exposé au dispositif intrautérin au lévonorgestrel durant 1 à 3 mois montre une augmentation très importante (11,5 fois) des petits vaisseaux non matures constitués exclusivement d'un endothélium. Le nombre de vaisseaux partiellement matures est augmenté de 6 fois. Au plus long cours, ces vaisseaux immatures ou partiellement matures restent néanmoins 4 fois plus fréquents que dans les endomètres non soumis à cette thérapeutique. La surface vasculaire et la densité augmentent au cours du temps sous ce dispositif hormonal (Stephanie et al. 2007). De telles modifications ne sont pas observées sous VA2914 et peuvent contribuer à l'absence de saignement. Au cours du cycle témoin, nous avons observé la présence de vaisseaux matures, représentant 80 % de la surface vasculaire totale. Après 3 mois de traitement sous VA2914 aux différentes doses, aucun changement vasculaire n'est observé. Sous VA2914, nous ne constatons pas de modification de l'expression du VEGFA ni de modification de sa distribution qui apparaît prédominante au niveau de la portion apicale des cellules épithéliales de surface et glandulaires. L'absence de modification de la distribution et de l'intensité du marquage du VEGFA (Vascular endothelial growth factor) et la stabilité du rapport Ang-1/Ang-2 avant et sous traitement par VA2914 n'est pas en faveur d'un remodelage vasculaire important (Ravet et al. 2009). Au niveau du réseau vasculaire endométrial, le VA2914 ne paraît donc pas se comporter comme un agoniste du récepteur de la progestérone.