Vitamin D3 Regulation of the Hypothalamic-Pituitary-Gonadal Axis

说明(申请人提供)：11-羟基酶(CYP27b1；将25-羟基维生素D3转化为最具活性的维生素D3的限速酶，1，25-二羟基维生素D3)和维生素D受体(VDR)是核激素受体超家族成员，广泛分布于许多器官系统，在调节骨骼健康、免疫系统、生长、分化和发育中发挥重要作用。最近的几项临床和实验室研究记录了维生素D3缺乏状态下的不育症或明显的不育症，表明维生素D3可能是正常生殖生理和生殖成功所必需的。维生素D3调节下丘脑-垂体-性腺轴的机制以及维生素D3缺乏如何对女性生育和生殖产生不利影响尚不清楚。VDR和CYP27b1基因敲除小鼠的表型包括性腺功能减退、卵巢卵泡发育受阻和子宫发育不全。在CYP27b1和VDR基因敲除小鼠中，子宫对外源性类固醇的反应是完整的，因此表明维生素D3缺乏损害了下丘脑-垂体-卵巢轴的一个或多个成分。这一探索性项目的目标是检验这样一种假设，即维生素D3缺乏会对生殖轴的神经内分泌(下丘脑-脑下垂体)成分产生不利影响，从而损害女性的生殖成功。拟议的实验将以缺乏活性1，25-二羟基维生素D3的CYP27b1基因敲除小鼠为模型，以阐明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。具体目标1确定正常卵巢生理是否需要1，25-(OH)2D3。我们将确定1，25-(OH)2D3缺乏是否会扰乱卵泡发育、卵巢类固醇的产生，或者使卵巢卵泡对促性腺激素的反应降低。特定目标2确定1，25-(OH)2D3缺乏是否会扰乱下丘脑-垂体轴功能。我们的初步数据显示，促性腺激素刺激卵泡发育和排卵，但缺乏维生素D3的CYP27b1基因缺失的雌性小鼠的青春期和第一次发情延迟，并且基因缺失的小鼠改变了发情周期。这些数据表明，维生素D3缺乏会对下丘脑-垂体的生理产生不利影响。因此，我们将重点关注神经内分泌功能，并系统分析维生素D3缺乏如何扰乱促性腺激素释放激素(GnRH)神经元和垂体促性腺激素细胞的功能，以及维生素D3缺乏的不良影响是否可逆。维生素D缺乏和缺乏在世界范围内已接近流行水平，青春期儿童和育龄妇女受到的影响不成比例。这些特定目标的完成将提供有关维生素D3在女性生殖中的调节作用的关键信息，并可能为维生素D3缺乏的妇女生殖成功率下降的机制提供洞察。 公共卫生相关性：维生素D3缺乏和不足是严重的公共卫生问题，影响多达36%的美国人口。重要的是，维生素D3缺乏对青春期儿童、育龄妇女、特别是贫穷妇女和有色人种妇女的影响不成比例，因此有可能对生殖功能和妊娠结局产生不利影响。拟议的实验将深入了解维生素D3调节女性生殖和生育的机制，重点是维生素D3缺乏对下丘脑-垂体-性腺轴完整性的影响。该项目可能为建立针对高危人群的筛查算法和开发相对安全、廉价、生物学上可信但简单的医疗干预措施提供基础，旨在消除差异，改善公共卫生结果，并减轻医疗费用负担。

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.