Vitamin D3 Regulation of the Hypothalamic-Pituitary-Gonadal Axis

维生素 D3 对下丘脑-垂体-性腺轴的调节

• 批准号: 8114370
• 负责人: Genevieve S. Neal-Perry
• 金额: $ 24.9万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114370
• 关键词: Adult; Adverse effects; Affect; African American; Agonist; Algorithms; Anguish; Binding; Calcifediol; Calcitriol; Child; Cholecalciferol; Clinical Research; Color; Data; Defect; Deposition; Development; Differentiation and Growth; Emotional; Enzymes; Epidemic; Epidemiologic Studies; Estradiol; Estrous Cycle; Estrus; Etiology; Family member; Feedback; Female; Fertility; Follicle Stimulating Hormone; Foundations; Functional disorder; Future; Glutamate Receptor; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth and Development function; Health; Health Care Costs; High Prevalence; Human; Hypogonadism; Hypothalamic structure; Immune system; Incidence; Infertility; Institution; Intervention; Knock-out; Knockout Mice; Laboratory Study; Lead; Ligands; Luteinizing Hormone; Mammalian Oviducts; Measures; Medical; Messenger RNA; Mixed Function Oxygenases; Modeling; Mus; N-Methylaspartate; Neonatal; Neurons; Neurosecretory Systems; Nuclear Hormone Receptors; Obesity; Oocytes; Outcome; Ovarian; Ovarian Follicle; Ovary; Ovulation; Phenotype; Physiology; Pilot Projects; Pituitary Gland; Population; Populations at Risk; Pregnancy Outcome; Primates; Production; Proteins; Puberty; Public Health; Regulation; Reporting; Reproduction; Reproductive Physiology; Rodent; Role; Screening procedure; Staging; Steroid biosynthesis; Steroids; Supplementation; Syndrome; Testing; Transgenic Mice; Translating; United States; Uterus; Vitamin D; Vitamin D3 Receptor; Woman; aged; body system; bone health; clinically significant; corpus luteum; experience; female reproductive system; folliculogenesis; hypothalamic pituitary axis; hypothalamic pituitary gonadal axis; hypothalamic pituitary ovarian axis; improved; insight; kisspeptin; low socioeconomic status; novel; reproductive; reproductive axis; reproductive function; reproductive success; research study; tool; transcription factor

DESCRIPTION (provided by applicant): The enzyme 11-hydroxylase (CYP27b1; the rate limiting enzyme converting 25-hydroxyvitamin D3 to the most active form of vitamin D3, 1,25-dihydroxyvitamin D3) and the vitamin D receptor (VDR), a nuclear hormone receptor super-family member, are distributed throughout many organ systems and have established roles in the regulation of bone health, the immune system, growth, differentiation and development. Several recent clinical and laboratory studies documenting either subfertility or frank infertility in vitamin D3 deficient states suggest that vitamin D3 may be essential for normal reproductive physiology and reproductive success. The mechanisms by which vitamin D3 regulates the hypothalamic-pituitary-gonadal axis and how vitamin D3 deficiency adversely affects female fertility and reproduction are not understood. Phenotypes in VDR and CYP27b1 knockout mice include hypogonadism, arrested ovarian follicular development and hypoplastic uteri. Uterine responsive to exogenous steroids is intact in CYP27b1 and VDR knockout mice, thus suggesting that vitamin D3 deficiency impairs one or more components of the hypothalamic-pituitary-ovarian axis. The goal of this exploratory project is to test the hypothesis that vitamin D3 deficiency compromises female reproductive success by adversely affecting the neuroendocrine (hypothalamic-pituitary) component of the reproductive axis. The proposed experiments will use CYP27b1 knockout mice, deficient in active 1,25-dihydroxyvitamin D3, as a model to elucidate the mechanisms through which peripubertal and adult vitamin D3 regulates the pubertal transition and the female reproductive system. Specific Aim 1 determines if 1,25-(OH)2D3 is required for normal ovarian physiology. We will determine if 1,25-(OH)2D3 deficiency disrupts follicular development, ovarian steroid production, or renders ovarian follicles less responsive to gonadotropins. Specific Aim 2 determines if 1,25-(OH)2D3 deficiency disrupts hypothalamic-pituitary axis function. Our preliminary data show that gonadotropins stimulate follicular development and ovulation, but that puberty and the first estrus are delayed in vitamin D3 deficient CYP27b1 null female mice and that null mice have altered estrous cycles. These data suggest that vitamin D3 deficiency adversely affects hypothalamic- pituitary physiology. Therefore, we will focus on neuroendocrine function and systematically analyze how vitamin D3 deficiency disrupts the function of gonadotropin releasing hormone (GnRH) neurons and of pituitary gonadotrophs and if the adverse effects of vitamin D3 deficiency is reversible. Vitamin D insufficiency and deficiency have reached near epidemic levels worldwide, with peripubertal children and reproductive aged women being disproportionately affected. Completion of these specific aims will provide critical information regarding the regulatory role of vitamin D3 in female reproduction and may provide insight into the mechanisms underlying reduced reproductive success in vitamin D3 deficient women. PUBLIC HEALTH RELEVANCE: Vitamin D3 deficiency and insufficiency are significant public health problems, affecting as much as 36% of the United States population. Importantly, vitamin D3 deficiency disproportionately affects peripubertal children, reproductive aged women, especially poor women and women of color, thus having the potential to adversely affect reproductive function and pregnancy outcomes. The proposed experiments will provide insight into the mechanisms through which vitamin D3 regulates female reproduction and fertility with a focus on the impact of vitamin D3 deficiency on the integrity of hypothalamic-pituitary-gonadal axis. This project may provide a foundation for the institution of screening algorithms for at risk populations and the development of a relatively safe, inexpensive, biologically plausible yet simple medical intervention intended to eliminate disparities, to improve public health outcomes, and to reduce the burden of health care costs.

DESCRIPTION (provided by applicant): The enzyme 11-hydroxylase (CYP27b1; the rate limiting enzyme converting 25-hydroxyvitamin D3 to the most active form of vitamin D3, 1,25-dihydroxyvitamin D3) and the vitamin D receptor (VDR), a nuclear hormone receptor super-family member, are distributed throughout many organ systems and have在调节骨骼健康，免疫系统，生长，分化和发育中确定了作用。最近的几项临床和实验室研究记录了维生素D3缺乏态度的亚生育或坦率的不育症，这表明维生素D3对于正常的生殖生理和生殖成功可能是必不可少的。维生素D3调节下丘脑 - 垂体 - 基达轴的机制以及维生素D3缺乏症如何不利地影响女性的生育能力和繁殖。 VDR和CYP27B1基因敲除小鼠中的表型包括性腺功能减退，捕获的卵巢卵泡发育和不塑性子宫。在CYP27B1和VDR基因敲除小鼠中，对外源类固醇反应的子宫完好无损，因此表明维生素D3缺乏会损害下丘脑 - 垂体 - 垂体 - 卵巢轴的一个或多个成分。该探索性项目的目的是检验以下假设：维生素D3缺乏症会通过不利影响生殖轴的神经内分泌（下丘脑 - 垂体）成分来损害女性生殖成功。所提出的实验将使用CYP27B1敲除小鼠，该小鼠缺乏活性1,25-二羟基维生素D3，以阐明围绕青春期和成年维生素D3调节青春期过渡和女性生殖系统的机制。特定目标1确定正常卵巢生理学是否需要1,25-（OH）2d3。我们将确定1,25-（OH）2d3缺陷是否会破坏卵泡发育，卵巢类固醇产生或使卵巢卵泡对促性腺激素的反应较低。具体目标2确定1,25-（OH）2d3缺陷是否会破坏下丘脑 - 垂体轴功能。我们的初步数据表明，促性腺激素会刺激卵泡发育和排卵，但青春期和第一个发情在维生素D3缺乏CYP27B1无效的雌性小鼠中延迟，而无效的小鼠已经改变了发育周期。这些数据表明，维生素D3缺乏对下丘脑 - 垂体生理的影响。因此，我们将关注神经内分泌功能，并系统地分析维生素D3缺乏症如何破坏促性腺激素释放激素（GNRH）神经元以及垂体促性腺营养性以及维生素D3缺乏症的不良影响的功能。维生素D的不足和缺乏症已在全球范围内接近流行病，围血儿童和生殖老年妇女受到了不成比例的影响。这些具体目标的完成将提供有关维生素D3在女性繁殖中调节作用的关键信息，并可以洞悉降低的维生素D3缺乏女性生殖成功的机制。 公共卫生相关性：维生素D3缺乏症和不足是严重的公共卫生问题，影响了美国人口的36％。重要的是，维生素D3缺乏症会影响围腹儿童，生殖老年妇女，尤其是贫困妇女和有色妇女，因此有可能对生殖功能和妊娠结局产生不利影响。提出的实验将提供有关维生素D3调节女性繁殖和生育力的机制的洞察力，重点是维生素D3缺乏对下丘脑 - 垂体 - 核轴轴完整性的影响。该项目可能为在风险人群中筛查算法的制度提供基础，并开发相对安全，廉价，生物学上可行而简单的医疗干预措施，旨在消除差异，改善公共卫生的结果并降低卫生保健成本的成本。