Il existe deux types de néoplasies vulvaires intra-épithéliales (VIN). La VIN classique (VINc) est induite par le papillomavirus humain (HPV) et se caractérise histologiquement par une surexpression de p16. La VIN différenciée (VINd) survient essentiellement sur un lichen scléreux vulvaire (LSV). Classiquement, ces deux voies de cancérogénèse se développent indépendamment l'une de l'autre, mais, en pratique courante, des cas de VINc peuvent survenir sur LSV. L'objectif de ce travail était de décrire l'association entre le LSV et les VINc. Cette étude rétrospective a porté sur les cas de VIN suivis en consultation multidisciplinaire de pathologie vulvaire du CHU de Lille, entre le 1er janvier 2008 et le 31 décembre 2018. Cent six patientes étaient atteintes de VIN, dont 78 VINc (73,6 %) et 28 VINd (26,4 %). Quarante patientes sur les 106 présentaient un LSV. Parmi les patientes atteintes de VINc, douze (15,4 %) étaient atteintes également d'un LSV. Ces douze patientes représentaient 30 % des VIN compliquant un LSV et 11,3 % de toutes les VIN. Leur âge médian au diagnostic était de 72 ans (58–77) et la moitié d'entre elles était traitée par dermocorticoïdes pour le LSV. Toutes les VINc sur LSV présentaient une immunoréactivité pour l'anticorps anti-p16, témoin de l'infection HPV (Figure 1). Les présentations cliniques les plus fréquentes de ces 12 patientes étaient des macules érythémateuses ou une leucoplasie (Figure 2). Ces lésions étaient unifocales ou multifocales et étaient localisées en majorité sur les petites lèvres (50 %). Deux de ces patientes (16,7 %) présentaient un carcinome épidermoïde invasif de manière concomitante. L'infection à HPV pourrait être favorisée par les dermocorticoïdes utilisés pour traiter le LSV. Cette hypothèse n'explique cependant pas toutes les infections car, pour moitié, nos patientes n'étaient pas traitées pour leur LSV avant le diagnostic de VINc. Il ne nous semble d'ailleurs pas judicieux de ne pas utiliser les dermocorticoïdes pour traiter le LSV, car même s'ils peuvent favoriser l'apparition de VINc, ils permettent de réduire la morbidité à long terme du LSV et peuvent éviter le risque de développement de CE invasifs HPV-négatifs. Les VINc survenant sur LSV ne sont pas rares, bien que l'association LSV et VINd ait la réputation d'être la plus classique. Des études prospectives permettraient de comprendre les mécanismes de cette association jusqu'alors peu rapportée.

Generating a precise cellular and molecular cartography of the human embryo is essential to our understanding of the mechanisms of organogenesis in normal and pathological conditions. Here, we have combined whole-mount immunostaining, 3DISCO clearing, and light-sheet imaging to start building a 3D cellular map of the human development during the first trimester of gestation. We provide high-resolution 3D images of the developing peripheral nervous, muscular, vascular, cardiopulmonary, and urogenital systems. We found that the adult-like pattern of skin innervation is established before the end of the first trimester, showing important intra- and inter-individual variations in nerve branches. We also present evidence for a differential vascularization of the male and female genital tracts concomitant with sex determination. This work paves the way for a cellular and molecular reference atlas of human cells, which will be of paramount importance to understanding human development in health and disease. PAPERCLIP.

L’endométriose, définie par la présence de tissu endométrial en dehors de la cavité utérine, est une pathologie fréquente mais souvent sous-diagnostiquée. Les manifestations cliniques sont variées (douleurs pelviennes chroniques, symptomatologie urinaire ou digestive) et peuvent être frustres, ce qui retarde le diagnostic. Ce retard au diagnostic et la chronicité des douleurs sont responsables d’un retentissement psychologique important chez ces patientes, parfois associé à un sentiment d’incompréhension et d’abandon par l’entourage et le corps médical. Ce climat de stress et d’anxiété peut être à l’origine de modifications du comportement et notamment de troubles sexuels, relationnels, mais également être responsable de conséquences socioprofessionnelles. L’endométriose peut être révélée dans le cadre d’un bilan d’infertilité, période pendant laquelle la patiente et le couple peuvent être fragilisés et la vie sexuelle déjà impactée. Le retentissement clinique et psychologique de l’endométriose entraîne inévitablement une altération de la qualité de vie des patientes et de leur sexualité. L’objectif de cet article est de faire le point sur les conséquences psychologiques de l’endométriose et sur son retentissement sur la sexualité, dans le but de mettre en avant ces aspects essentiels à prendre en compte pour une prise en charge globale des patientes.

Chronic disease impacts on patients' quality of life and in particular their sexuality. The consequences on their sexual quality of life are both physical and psychological and also affect their relationship as a couple. The issue is still taboo with too few caregivers prepared to address it.

Fertility in mammals is controlled by hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH). These neurons differentiate in the olfactory placodes during embryogenesis and migrate from the nose to the hypothalamus before birth. Information regarding this process in humans is sparse. Here, we adapted new tissue-clearing and whole-mount immunohistochemical techniques to entire human embryos/fetuses to meticulously study this system during the first trimester of gestation in the largest series of human fetuses examined to date. Combining these cutting-edge techniques with conventional immunohistochemistry, we provide the first chronological and quantitative analysis of GnRH neuron origins, differentiation and migration, as well as a 3D atlas of their distribution in the fetal brain. We reveal not only that the number of GnRH-immunoreactive neurons in humans is significantly higher than previously thought, but that GnRH cells migrate into several extrahypothalamic brain regions in addition to the hypothalamus. Their presence in these areas raises the possibility that GnRH has non-reproductive roles, creating new avenues for research on GnRH functions in cognitive, behavioral and physiological processes.

Endometriosis, defined by the presence of endometrial tissue outside the uterine cavity, is a common but often under diagnosed pathology. The clinical manifestations are varied (chronic pelvic pain, urinary or gastrointestinal symptoms) and can sometimes be very frustrated, delaying the diagnosis. This delay in diagnosis can be a high source of stress responsible for an important psychological impact in these patients, having a sense of misunderstanding and neglect of the medical profession. This climate of stress and anxiety can cause alteration of behavior including sexual disorders. In addition, endometriosis can be revealed as part of an infertility evaluation, and the patient and the couple can already be affected by this situation. The clinical and psychological impact of endometriosis inevitably leads to an impairment of patient's quality of life and sexuality. The objective of this article is to show the psychological consequences of endometriosis and its impact on sexuality, in order to highlight this essential aspect for a comprehensive care of patients. (C) 2016 Elsevier Masson SAS. All rights reserved.

Objective. - This work aims to discuss the hypothesis by which spontaneous vulvodynia etiology is psychosomatic, and to suggest some suitable therapeutic angles.Method. - The data for this work essentially stems from the authors' clinical experience, in particular within the framework of multidisciplinary consultations for vulvar pathology. The resulting hypotheses are confirmed by scientific works quoted in reference.Results. - Everyone seems to agree today on the definition of vulvodynia. This however covers a whole host of very different situations, including generalized spontaneous vulvodynia (GVD), which is without question the hardest one to diagnose and treat. Numerous arguments lead the authors of this work to believe that a psychosomatic origin is the most likely. To appear, GVD requires the association of 3 parameters: firstly a personality dominated by anxiety, sometimes, even depression, secondly a local or psychological triggering factor, and finally an underlying sexological problem. The symptoms of GVD always have a significant negative impact on the patient's quality of life and this in turn generates ever more anxiety, especially as most practitioners are not very familiar with it and can neither explain it, nor offer a logical and effective treatment. No simple therapeutic approach has ever been able to demonstrate its efficacy and, in the authors' opinion, never will. Any therapeutic approach for this problem will inevitably be complex and multidisciplinary, and must include in particular a psychosexological element, which will integrate work on the body.Conclusion. - GVD must no longer remain a mysterious set of symptoms that cause a major deterioration in the patient's quality of life, whilst puzzling and confusing the medical profession. However, it is a complex disease, and its treatment has to be multidisciplinary and long-term, including a significant psychosexological dimension. (C) 2016 Elsevier Masson SAS. All rights reserved.

Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS.

Il existe une importante comorbidité entre dysfonction sexuelle (DS) et dépression avec des liens de causalité bidirectionnelle.En effet, la guérison du syndrome dépressif améliore la DS, en particulier la libido, tout comme le traitement efficace d'une DS entraîne une amélioration thymique.Cependant, la plupart des antidépresseurs peuvent induire à leur tour des DS, ce qui constitue un facteur fréquent de non observance de ces traitements.Cet article passe en revue ces différents problèmes, dont le corps médical ne peut plus ignorer l'importance en pratique clinique.The mutually reinforcing dyad of depressive symptoms and erectile dysfunction is scientifically established.The cure of depression improves sexual dysfunction (SD) and the treatment of SD induces improvement of depression.Most of anti-depressants induce negative sexual side effects that lead to non-compliance of these treatments.The knowledge of interrelation between depression, anti-depressants and sexuality is of great importance in clinical practice.

En passant d’un statut d’outil à celui d’un nouveau mode de travail, l’Evidence Based Medicine (EBM) et l’intelligence artificielle (IA) sont à l’origine de disruptions majeures dans le monde de la santé, y compris sexuelle. Plusieurs disruptions la concernent : (1) s’en préoccuper peut améliorer la qualité mais aussi la quantité de vie des malades chroniques, (2) le concept de santé sexuelle positive doit être développé et favorisé, (3) la santé sexuelle contribue à restaurer la clinique et l’humanisme inhérents à la culture soignante. Nouveau déterminant de santé, de bien-être et de qualité de vie, elle doit être désormais intégrée dans les parcours de soins et de vie des malades chroniques pour répondre à leurs besoins émotionnels et médicaux, et à deux priorités de santé publique : réduire les inégalités de soins et améliorer leur pertinence. Une majorité de malades souhaite préserver ou récupérer ce facilitateur de lien social et de résilience mais la réponse soignante est globalement insuffisante. Le manque de connaissances et les idées reçues expliquent le défaut d’appropriation de la santé sexuelle et de ses troubles par les professionnels de santé. Malgré l’apport indéniable de l’EBM et de l’IA, la clinique, meilleur moyen jusqu’à présent pour les évaluer, reste primordiale pour atteindre l’objectif majeur des soins « centrés sur la personne » : concilier le « cure » (capacité de guérir/relation technique) et le « care » (capacité de prendre soin d’autrui/relation humaine). Prendre en compte la santé sexuelle et ses disruptions, en cours ou à venir, dans les parcours de soins devient une obligation déontologique pour se recentrer sur les fondamentaux éthiques de la médecine soignant une personne, en respectant son autonomie et sa dignité. Dans ce but, la sexologie doit devenir une compétence transdisciplinaire médicale et paramédicale pour favoriser une réappropriation soignante de la clinique et de l’humanisme.By becoming a new working mode, evidence based medicine (EBM) and artificial intelligence (AI) are at the origin of major disruptions in the health world including sexual one's. Several disruptions concern it: (1) its assessment may improve the quality but also the amount of life of chronic diseases patients, (2) the concept of positive sexual health must be developed and promoted, (3) sexual health contributes to restore the clinical and humanism inherent in the caring culture. As a new determinant of health, well-being and quality of life, sexual health must from now be integrated into both care pathways and chronic diseases patients life. This responds to emotional and medical needs of patients as well as to two public health priorities: reducing health care inequalities and improving their relevance. A majority of patients want to preserve or to recover this social link and resilience facilitator, but the health care response generally is inadequate. A lack of knowledge and received ideas explain the appropriation failure of sexual health and its disorders by health care professionals. Despite the undeniable contribution of EBM and AI, the clinic, the best way so far to evaluate them, remains paramount to achieving a major goal of “person-centered care”: to reconcile the “cure” (ability to cure/technical relation) and the “care” (ability to take care of others/human relationship). Taking into account sexual health and its disruptions (ongoing or forthcoming in progress or in the future) in the health care pathways is thus becoming a deontological obligation. It aims to refocus on the ethics fundamentals of medicine caring a person respecting his autonomy and dignity. To this end, sexology must become a transdisciplinary medical and paramedic competence to promote a careful reappropriation of the clinic and humanism.

Le but de ce travail est d’apprécier le retentissement osseux de l’anorexie mentale en termes épidémiologiques, diagnostiques, physiopathologiques et de tenter d’en évaluer les conséquences thérapeutiques. La perte osseuse de l’anorexie mentale est d’autant plus grande que la maladie apparaît précocement dans l’adolescence et que la durée de l’aménorrhée est importante. Elle est responsable d’une ostéoporose dans 38 à 50 % des cas. L’évaluation du retentissement osseux de l’anorexie mentale peut être réalisée grâce à la mesure de la densité minérale osseuse par absorptiométrie biphotonique à rayons X. L’étude des marqueurs osseux permet également d’apprécier le niveau de remodelage osseux de ces patientes. Le mécanisme de cette perte osseuse semble complexe. Le déficit en estrogènes a longtemps été incriminé comme facteur principal mais il ne peut l’expliquer à lui seul. En effet, contrairement à l’ostéoporose postménopausique, la perte osseuse de ces patientes est plutôt due à une diminution de la formation avec une résorption discrètement augmentée. Ceci suggère le rôle essentiel de la dénutrition et des facteurs liés à la nutrition en particulier de l’axe hormone de croissance–somatomédine C (GH-IGF-I). La prise en charge thérapeutique de l’atteinte osseuse de l’anorexie mentale reste discutée. Si le retour des règles et la récupération pondérale semblent indispensables, ils ne permettent pas toujours de corriger cette perte osseuse. Les différentes études n’ont pas montré d’efficacité du traitement par estrogènes mais celui-ci était administré sous forme de pilules estroprogestatives le plus souvent. Aucune étude de grande ampleur n’a été réalisée avec un traitement hormonal substitutif. Les meilleurs résultats semblent être obtenus avec des traitements ostéoformateurs comme l’IGF-I surtout associés aux estrogènes. Ceci laisse présager l’apparition de stratégies thérapeutiques complexes faisant appel à des traitements ostéoformateurs et antirésorptifs dans cette indication.

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.

Glioblastomas are the most common primary central nervous system tumors in adults, and they remain resistant to current treatments. erbB1 signaling is frequently altered in glioblastomas, suggesting that erbB receptor family members may represent targets for molecular therapy. We performed a comprehensive analysis of erbB receptor and ligand expression profiles in a panel of 9 glioblastomas and compared them to nonneoplastic cerebral tissue containing neocortex and adjacent white matter. Quantitative reverse transcription-polymerase chain reaction and Western blot analysis showed that erbB1 signaling and erbB2 receptors exhibited highly variable deregulation profiles in the tumors, with patterns ranging from under-expression to overexpression; in contrast, erbB3 and erbB4 were downregulated. We next performed immunohistochemistry to determine the distribution patterns of erbB receptors among the main neural cell types in the tumors with special reference to the putative tumor stem cell population. Results revealed intertumoral and intratumoral heterogeneity in all 4 erbB expression profiles, but each receptor exhibited a distinct distribution pattern among glial fibrillary acidic protein-, Olig2-, NeuN-, and CD133-positive populations. Although erbB1 immunoreactivity was detected in only small subsets of CD133-positive putative tumor stem cells, erbB3 immunoreactivity was prominent in this population, suggesting that erbB3 may represent a new potential therapeutic target.

Studies in rodents have shown that astroglial erbB tyrosine kinase receptors are key regulatory elements in neuron–glia communication. Although both astrocytes and deregulation of erbB functions have been implicated in the pathogenesis of many common human brain disorders, erbB signaling in native human brain astrocytes has never been explored. Taking advantage of our ability to perform primary cultures from the cortex and the hypothalamus of human fetuses, we conducted a thorough analysis of erbB signaling in human astrocytes. We showed that human cortical astrocytes express erbB1, erbB2, and erbB3, whereas human hypothalamic astrocytes express erbB1, erbB2, and erbB4 receptors. Ligand‐dependent activation of different erbB receptor heterodimeric complexes in these two populations of astrocytes translated into different morphological and proliferative responses. Although morphological plasticity was more pronounced in hypothalamic astrocytes than in cortical astrocytes, the former showed a lower mitogenic potential. Decreasing erbB4 expression via siRNA‐mediated gene knockdown revealed that erbB4 constitutively restrains basal proliferative activity in hypothalamic astrocytes. We further show that treatment of human astrocytes with a protein kinase C activator results in rapid tyrosine phosphorylation of erbB receptors that involves cleavage of endogenous membrane bound erbB ligands by metalloproteinases. Together, these results indicate that erbB signaling in primary human brain astrocytes is functional, region‐specific, and can be activated in a paracrine and/or autocrine manner. In addition, by revealing that some aspects of astroglial erbB signaling are different between human and rodents, our results provide a molecular framework to explore the potential involvement of astroglial erbB signaling deregulation in human brain disorders. © 2008 Wiley‐Liss, Inc.

The purpose of this longitudinal study was to evaluate factors affecting changes in bone mineral density (BMD) in patients with anorexia nervosa (AN) and osteoporosis and, more particularly, to assess the benefits of hormone replacement therapy (HRT) on BMD in these patients. Our study involved 45 AN patients, 12 of whom had been treated by HRT for 2 years following a diagnosis of osteoporosis by densitometry (WHO criteria). Patients’ mean age was 25.3 ± 6.7 years. Mean duration of illness was 5.7 ± 5.3 years. Serum calcium and phosphate were measured at baseline, as were bone remodeling markers. Osteodensitometry by dual-energy X-ray absorptiometry was performed at inclusion and after 2 years. After 2 years, no significant differences were observed between spine, femoral neck, and total hip BMDs either in the HRT group (P = 0.3, P = 0.59, P = 0.58) or in the nontreatment group (P = 0.17, P = 0.68, P = 0.98). Moreover, there were no significant differences between the two groups when changes in spine, femoral neck, and total hip BMDs at 2 years were compared (P = 0.72, P = 0.95, P = 0.58). In both groups, change in weight at 1 year correlated with change in spine BMD at 2 years (r = 0.35, P = 0.04) and change in total-hip BMD at 2 years (r = 0.35, P = 0.04) but not with change in femoral neck BMD at 2 years. Patients with a body mass index (BMI) ≥ 17 kg/m2 at 2 years showed a significant increase in total-hip BMD when compared with patients with a BMI < 17 kg/m2 (+4.4% ± 6.7 vs. −0.5% ± 6.01, P = 0.03). No significant differences were observed for spine and femoral neck BMD. In patients who had recovered their menstrual cycle, significant increases were observed in spine BMD (+4% ± 6.3 vs. −1.9% ± 5.6, P = 0.008), femoral neck BMD (+3% ± 6.2 vs. −2.4% ± 8, P = 0.05), and total-hip BMD (+3% ± 7.1 vs. −3.7% ± 10, P = 0.04). Prevention of bone loss at 2 years in AN patients treated by HRT was not confirmed in this study. We did confirm that increase in weight at 1 year was the most predictive factor for the improvement of spine and hip BMD at 2 years.