RESUMO
Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and sexual satisfaction. While the hypothalamus is known to regulate sexual behavior, the specific neuronal pathways affected in patients with PCOS are not known. To dissect the underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal PCOS features. We discovered that female mice prenatally treated with anti-Müllerian hormone (PAMH) display impaired sexual behavior and sexual partner preference over the reproductive age. Blunted female sexual behavior was associated with increased sexual rejection and independent of sex steroid hormone status. Structurally, sexual dysfunction was associated with a substantial loss of neuronal nitric oxide synthase (nNOS)-expressing neurons in the ventromedial nucleus of the hypothalamus (VMH) and other areas of hypothalamic nuclei involved in social behaviors. Using in vivo chemogenetic manipulation, we show that nNOSVMH neurons are required for the display of normal sexual behavior in female mice and that pharmacological replenishment of nitric oxide restores normal sexual performance in PAMH mice. Our data provide a framework to investigate facets of hypothalamic nNOS neuron biology with implications for sexual disturbances in PCOS.
Assuntos
Óxido Nítrico Sintase Tipo I , Óxido Nítrico , Síndrome do Ovário Policístico , Comportamento Sexual , Núcleo Hipotalâmico Ventromedial , Animais , Hormônio Antimülleriano/farmacologia , Modelos Animais de Doenças , Feminino , Preferência de Acasalamento Animal , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Síndrome do Ovário Policístico/enzimologia , Síndrome do Ovário Policístico/fisiopatologia , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/metabolismoRESUMO
Fertilization is a complex process that requires successive stages and culminates in the adhesion/fusion of gamete membranes. If the question of the involvement of oocyte integrins has been swept away by deletion experiments, that of the involvement of sperm integrins remains to be further characterized. In the present study, we addressed the question of the feasibility of sperm-oocyte adhesion/fusion and early implantation in the absence of sperm ß1 integrin. Males and females with ß1 integrin-depleted sperm and oocytes were mated, and fertilization outcome was monitored by a gestational ultrasound analysis. Results suggest that although the sperm ß1 integrin participates in gamete adhesion/fusion, it is dispensable for fertilization in mice. However, sperm- and/or oocyte-originated integrin ß1 is essential for post-implantation development. Redundancy phenomena could be at the origin of a compensatory expression or alternative dimerization pattern.
Assuntos
Integrina beta1 , Interações Espermatozoide-Óvulo , Feminino , Camundongos , Masculino , Animais , Integrina beta1/genética , Integrina beta1/metabolismo , Sêmen/metabolismo , Oócitos/metabolismo , Espermatozoides/metabolismo , Fertilização , Integrinas/metabolismoRESUMO
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood. However, the underlying mechanisms of its transmission remain unknown, thus limiting the development of effective therapeutic strategies.This article highlights how an altered fetal environment (prenatal exposure to high levels of anti-Müllerian hormone) can contribute to the onset of PCOS in adulthood and lead to the transgenerational transmission of neuroendocrine and metabolic traits through alterations in the DNA methylation process.The originality of the translational findings summarized here involves the identification of potential biomarkers for early diagnosis of the syndrome, in addition to the validation of a promising therapeutic avenue in a preclinical model of PCOS, which can improve the management of patients suffering from the syndrome.
Le syndrome des ovaires polykystiques (SOPK) est le trouble endocrinien et métabolique le plus répandu chez les femmes en âge de procréer, avec une forte composante héréditaire estimée entre 60 et 70%. Les facteurs environnementaux pendant la période fÅtale pourraient être impliqués dans l'apparition du syndrome à l'âge adulte. Néanmoins, les mécanismes sous-jacents à sa transmission demeurent inconnus, limitant ainsi le développement de thérapies efficaces.Cet article met en lumière comment un environnement fÅtal altéré (exposition prénatale à des taux élevés d'hormone anti-müllerienne) pourrait contribuer à la survenue du SOPK chez la descendance ainsi qu'à la transmission transgénérationnelle des caractéristiques neuroendocriniennes et métaboliques du SOPK, par le biais d'une altération du processus de la méthylation de l'ADN.L'originalité des travaux translationnels présentés ici repose d'une part sur l'identification de potentiels biomarqueurs de diagnostic précoce du syndrome. Et d'autre part, sur la validation d'une piste thérapeutique prometteuse dans un modèle préclinique de SOPK, offrant ainsi des perspectives d'amélioration de la prise en charge des patientes atteintes de ce syndrome.
Assuntos
Síndrome do Ovário Policístico , Gravidez , Feminino , Humanos , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/genética , Fenótipo , Hormônio Antimülleriano , ReproduçãoRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder affecting between 5 and 18% of women worldwide. An elevated frequency of pulsatile luteinizing hormone (LH) secretion and higher serum levels of anti-Müllerian hormone (AMH) are frequently observed in women with PCOS. The origin of these abnormalities is, however, not well understood. METHODS: We studied brain structure and function in women with and without PCOS using proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging combined with fiber tractography. Then, using a mouse model of PCOS, we investigated by electron microscopy whether AMH played a role on the regulation of hypothalamic structural plasticity. FINDINGS: Increased AMH serum levels are associated with increased hypothalamic activity/axonal-glial signalling in PCOS patients. Furthermore, we demonstrate that AMH promotes profound micro-structural changes in the murine hypothalamic median eminence (ME), creating a permissive environment for GnRH secretion. These include the retraction of the processes of specialized AMH-sensitive ependymo-glial cells called tanycytes, allowing more GnRH neuron terminals to approach ME blood capillaries both during the run-up to ovulation and in a mouse model of PCOS. INTERPRETATION: We uncovered a central function for AMH in the regulation of fertility by remodeling GnRH terminals and their tanycytic sheaths, and provided insights into the pivotal role of the brain in the establishment and maintenance of neuroendocrine dysfunction in PCOS. FUNDING: INSERM (U1172), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n° 725149), CHU de Lille, France (Bonus H).
Assuntos
Síndrome do Ovário Policístico , Humanos , Animais , Camundongos , Feminino , Hormônio Luteinizante , Hormônio Antimülleriano , Imagem de Tensor de Difusão , Hormônio Liberador de Gonadotropina , Neuroglia/patologiaRESUMO
Mice are the most commonly used model animals for itch research and for development of anti-itch drugs. Most laboratories manually quantify mouse scratching behavior to assess itch intensity. This process is labor-intensive and limits large-scale genetic or drug screenings. In this study, we developed a new system, Scratch-AID (Automatic Itch Detection), which could automatically identify and quantify mouse scratching behavior with high accuracy. Our system included a custom-designed videotaping box to ensure high-quality and replicable mouse behavior recording and a convolutional recurrent neural network trained with frame-labeled mouse scratching behavior videos, induced by nape injection of chloroquine. The best trained network achieved 97.6% recall and 96.9% precision on previously unseen test videos. Remarkably, Scratch-AID could reliably identify scratching behavior in other major mouse itch models, including the acute cheek model, the histaminergic model, and a chronic itch model. Moreover, our system detected significant differences in scratching behavior between control and mice treated with an anti-itch drug. Taken together, we have established a novel deep learning-based system that could replace manual quantification for mouse scratching behavior in different itch models and for drug screening.
Assuntos
Aprendizado Profundo , Camundongos , Animais , Prurido/induzido quimicamente , Comportamento Animal , Injeções , Cloroquina/farmacologia , Modelos Animais de DoençasRESUMO
Here, we describe a protocol that provides the steps required for the generation of a mouse model of polycystic ovary syndrome (PCOS) by exposing dams to elevated levels of anti-Müllerian hormone during late gestation. This protocol also describes the steps required to assess the PCOS-like equivalents of the Rotterdam PCOS diagnostic criteria in mice. For complete details on the use and execution of this protocol, please refer to Tata et al. (2018) and Mimouni et al. (2021).
Assuntos
Hormônio Antimülleriano/efeitos adversos , Modelos Animais de Doenças , Síndrome do Ovário Policístico/fisiopatologia , Animais , Feminino , Camundongos , Hormônios Peptídicos/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologiaRESUMO
Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects. These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy.
Assuntos
Epigênese Genética , Síndrome do Ovário Policístico/genética , Animais , Hormônio Antimülleriano/farmacologia , Hormônio Antimülleriano/uso terapêutico , Estudos de Casos e Controles , Metilação de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Humanos , Hormônio Luteinizante/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigenases de Função Mista/genética , Ovário/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/patologia , Cuidado Pré-Natal , Proteínas Proto-Oncogênicas/genética , S-Adenosilmetionina/farmacologia , S-Adenosilmetionina/uso terapêutico , Transcriptoma/efeitos dos fármacosRESUMO
Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.
Assuntos
Hormônio Antimülleriano/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hipogonadismo/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Hormônio Antimülleriano/genética , Axônios/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Células COS , Movimento Celular , Chlorocebus aethiops , Feminino , Fertilidade , Feto/metabolismo , Heterozigoto , Humanos , Mutação com Perda de Função , Hormônio Luteinizante/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Bulbo Olfatório/metabolismo , Linhagem , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Adulto JovemRESUMO
Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.