Neuroendocrine Actions of Androgens in Female Reproduction

雄激素在女性生殖中的神经内分泌作用

• 批准号: 8809606
• 负责人: PAMELA L MELLON
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8809606
• 关键词: Address; Affect; Androgen Receptor; Androgens; Anovulation; Brain; Cells; Chronic; Disease; Endocrine System Diseases; Enzymes; Estrous Cycle; Feedback; Female; Fertility; Functional disorder; Gene Expression; Genetic; Goals; Gonadal Steroid Hormones; Gonadotropins; Hormones; Hyperandrogenism; Hypothalamic structure; In Vitro; Individual; Knowledge; Location; Luteinizing Hormone; Mediating; Modeling; Molecular Genetics; Molecular Profiling; Mus; Neuroendocrine Cell; Neurons; Neurosecretory Systems; Obesity; Ovarian; Ovulation; Phenotype; Physiologic pulse; Physiological; Physiology; Pituitary Gland; Play; Polycystic Ovary Syndrome; Progesterone; Progesterone Receptors; Receptor Signaling; Regulation; Reproduction; Reproductive Physiology; Resistance; Role; Series; Signal Transduction; System; Technology; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Woman; Work; cell type; genetic manipulation; hypothalamic pituitary ovarian axis; in vivo; innovation; kisspeptin; male; mouse model; novel; public health relevance; reproductive; reproductive function; reproductive hormone; response

 DESCRIPTION (provided by applicant): Androgen receptor signaling is crucial for normal female reproduction and hyperandrogenemia is a fundamental aspect of the reproductive disruption seen in Polycystic Ovary Syndrome (PCOS). Either lack of androgen receptor or androgen excess disrupts normal ovulation and neuroendocrine control of female reproduction, but the mechanisms for these effects are unknown. Our overall hypotheses are: 1) androgens acting in the brain and pituitary play an important role in regulating normal female fertility, and2) excess androgens, acting through androgen receptor in the hypothalamus and pituitary, are responsible for the neuroendocrine hallmarks of PCOS: high LH, low FSH, and progesterone (P4) resistance. We will test these hypotheses in a series of three independent but interrelated Aims that focus on the role of physiological androgen signaling and androgen excess in the hypothalamus and pituitary, using a combination of genetic and androgen-excess mouse models. Approaches will utilize genetic manipulation of androgen and P4 signaling in specific cell types in normal female mice and in a novel mouse model of obese PCOS. Aim 1 will focus on the brain by assessing whether androgen receptor (AR) is required specifically in neurons for normal female reproduction and for the deleterious effects of androgen excess. Using Cre-loxP technology, AR will be selectively deleted from brain neurons, and subsequently specifically from kisspeptin neurons. Females lacking AR in these neurons will be investigated for resistance to the effects of androgen excess in the new PCOS mouse model. Aim 2 will focus on the pituitary, with the hypothesis that excess androgens act directly at the gonadotrope to dysregulate LHβ and FSHβ and gonadotropin secretion in females. Female mice lacking AR selectively in the gonadotrope will be studied for altered reproductive function and gonadotropin secretion and in response to excess androgens in the PCOS mouse model. We will use primary pituitary cells in an innovative GnRH pulse system to directly test the actions of androgens on basal and GnRH-induced pulses of LH and FSH and gonadotropin gene expression. Aim 3 will test whether androgen excess interferes with P4 feedback at the hypothalamus and pituitary, as one attribute of PCOS women is impaired P4 feedback. We will determine if progesterone receptor (PR) is regulated by androgen excess in neuroendocrine tissues and whether P4 feedback is impaired by the actions of excess androgens. We will then remove PR selectively from brain neurons, kisspeptin neurons, or pituitary gonadotropes to investigate which cells mediate P4 negative feedback and the alterations caused by androgen excess. Together, these Aims will elucidate the role of AR and PR in the neuroendocrine system in normal female reproduction and illuminate the role of excess androgens in the dysregulation of neuroendocrine control of reproduction.

 描述（由申请人提供）：雄激素受体信号传导对正常女性生殖至关重要，高雄激素血症是多囊卵巢综合征（PCOS）中观察到的生殖中断的基本方面。雄激素受体缺乏或雄激素过量会干扰正常排卵和女性生殖的神经内分泌控制，但这些影响的机制尚不清楚。我们的总体假设是：1）作用于脑和垂体的雄激素在调节正常女性生育力中起重要作用，2）过量的雄激素通过下丘脑和垂体中的雄激素受体起作用，导致PCOS的神经内分泌标志：高LH、低FSH和孕酮（P4）抵抗。我们将在一系列三个独立但相互关联的目标中测试这些假设，这些目标集中在下丘脑和垂体中生理雄激素信号传导和雄激素过量的作用，使用遗传和雄激素过量小鼠模型的组合。方法将利用遗传操纵雄激素和P4信号在特定类型的细胞在正常雌性小鼠和肥胖PCOS的新小鼠模型。目的1将集中在大脑中，通过评估雄激素受体（AR）是否需要特别是在神经元正常的女性生殖和雄激素过量的有害影响。使用Cre-loxP技术，AR将选择性地从脑神经元中删除，随后特异性地从kisspeptin神经元中删除。将在新的PCOS小鼠模型中研究这些神经元中缺乏AR的雌性对雄激素过量影响的抗性。目的2将关注垂体，假设过量的雄激素直接作用于促性腺细胞，导致女性LHβ和FSHβ以及促性腺激素分泌失调。将研究在促性腺激素中选择性缺乏AR的雌性小鼠的生殖功能和促性腺激素分泌的改变以及对PCOS小鼠模型中过量雄激素的反应。我们将在一个创新的GnRH脉冲系统中使用原代垂体细胞，直接测试雄激素对LH和FSH的基础和GnRH诱导脉冲以及促性腺激素基因表达的作用。目标3将测试雄激素过多是否会干扰下丘脑和垂体的P4反馈，因为PCOS女性的一个属性是P4反馈受损。我们将确定孕激素受体（PR）是否受神经内分泌组织中雄激素过量的调节，以及P4反馈是否受过量雄激素的作用损害。然后，我们将选择性地从脑神经元、kisspeptin神经元或垂体促性腺激素细胞中去除PR，以研究哪些细胞介导P4负反馈和雄激素过量引起的改变。总之，这些目标将阐明AR和PR在正常女性生殖的神经内分泌系统中的作用，并阐明过量雄激素在生殖神经内分泌控制失调中的作用。