Vitamin D3 Regulation of the Hypothalamic-Pituitary-Gonadal Axis

描述（由申请人提供）：酶11-羟化酶（CYP27b1；将25-羟基维生素D3转化为维生素D3最活性形式的限速酶，1,25-二羟基维生素D3）和维生素D受体（VDR），核激素受体超家族成员，分布在许多器官系统中，并在骨骼健康，免疫系统，生长，分化和发育的调节中发挥作用。最近的一些临床和实验室研究记录了维生素D3缺乏状态下的低生育能力或直接不孕，表明维生素D3可能对正常的生殖生理和生殖成功至关重要。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，这表明维生素D3缺乏损害了下丘脑-垂体-卵巢轴的一个或多个组成部分。这个探索性项目的目标是测试维生素D3缺乏通过对生殖轴的神经内分泌（下丘脑-垂体）部分产生不利影响而损害女性生殖成功的假设。本实验将以CYP27b1基因敲除缺乏活性1,25-二羟基维生素D3的小鼠为模型，阐明青春期和成年期维生素D3调节青春期过渡和雌性生殖系统的机制。特异性目标1确定是否125 -(OH)2D3是正常卵巢生理所必需的。我们将确定125 -(OH)2D3缺乏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减弱。特异性目标2确定1.25 -(OH)2D3缺乏是否破坏下丘脑-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，但在缺乏维生素D3的雌性小鼠中，青春期和第一次发情延迟，并且没有CYP27b1的小鼠的发情周期发生了改变。这些数据表明维生素D3缺乏对下丘脑-垂体生理有不利影响。因此，我们将重点关注神经内分泌功能，系统分析维生素D3缺乏如何破坏促性腺激素释放激素（GnRH）神经元和垂体促性腺激素的功能，以及维生素D3缺乏的不良影响是否可逆。维生素D不足和缺乏症在全世界已接近流行病的程度，青春期周边儿童和育龄妇女受到的影响尤为严重。这些具体目标的完成将提供关于维生素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缺乏女性生殖成功率降低的机制提供见解。

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.