Oxidative Stress, Hormones and Women s Health

作为有氧生活的一部分，我们氧化大量的生物分子来获得化学能。在这个过程中，会形成几个中间体；有些是化学不稳定的，被称为自由基(FR)。FR往往与周围的生物环境快速反应；根据受到攻击的分子的性质，可能会发生不同的反应，即脂质过氧化、蛋白质氧化或DNA氧化产物。随着有氧生物的进化，针对FR的抗氧化防御系统已经发展起来。FR(氧化剂)的产生和抵抗它们(抗氧化剂)的防御系统之间的失衡导致氧化应激。这可能导致不可逆转的生化变化，从而导致组织损伤和疾病。 氧自由基与自然流产、男性和女性不孕不育、出生体重减轻、衰老以及心血管疾病和癌症等慢性病过程有关。虽然氧化应激与女性生育能力相关的机制还不完全清楚，但最近的动物和人类研究表明，氧化应激可能在卵泡生长、子宫内膜异位症的发生和子宫内膜血管生成的调节中发挥重要作用。微量营养素抗氧化剂、激素和酶类抗氧化剂能够中和氧自由基，抑制氧化，从而潜在地降低不孕症的风险。 已经开发了许多方法来测量组织、细胞和体液中的脂质过氧化产物和脂质过氧化损伤。脂质过氧化的标志物可以直接测量，也可以通过测量反应过程中涉及的任何物质来测量。由于自由基物种是损伤细胞的实际致病物质，因此直接测定其含量更适合于临床诊断。然而，自由基物种迅速消失，产生稳定的初级和次级脂质过氧化产物。尽管脂质过氧化与许多健康结果有关，但研究人员对于应该使用哪种方法来评估循环中的脂质过氧化水平仍存在很大分歧，这使得综合研究结果变得困难。 最近的研究表明，血浆脂蛋白水平在月经周期过程中会有波动。脂蛋白的这种周期性波动与血浆抗氧化剂浓度的波动有关。本文对12名健康女性月经周期各期的激素、脂蛋白、α-生育酚和类胡萝卜素进行了连续2~3天的同步测定。类胡萝卜素在月经期最低，叶黄素/玉米黄质及其代谢物脱水叶黄素的浓度在所有三个阶段(卵泡早期、卵泡晚期和黄体)都高于月经期。血浆胡萝卜素浓度在卵泡晚期达到峰值，而番茄红素、植酸烯、植物荧烯和视黄醇浓度在黄体期达到峰值。 排卵妇女在月经周期的卵泡期和黄体期，雌二醇和孕酮的循环水平也有波动。雌激素是一种强大的抗氧化剂，会影响女性的氧化应激和同型半胱氨酸水平。然而，关于氧化应激和雌激素水平之间的关系以及它们对结局的影响，如怀孕或自然流产的可能性，人们知之甚少。在评估这种关系之前，关键是要对氧化应激进行标准化测量，并知道它们随激素水平的变化而变化。这项研究的主要目标是更好地了解月经周期中激素水平和氧化应激(即雌激素、孕酮、黄体生成素等)之间的复杂关系。更具体地说，我们将研究：(I)氧化应激的周期内变化；(Ii)绝经前妇女月经周期中激素水平与氧化应激的关系；以及(Iii)吸烟、饮酒和锻炼等外部因素对氧化应激和激素水平的影响。 研究设计：一项针对250名女性的前瞻性纵向队列研究正在一所大学进行。对参与者进行筛查测试，以排除怀孕和/或患有无症状衣原体的妇女。招聘期将持续长达一整历年，以考虑到季节性变化。从月经周期的第一天到月经结束，参与者被跟踪两个月经周期，每隔一段时间采集血液和尿液样本，与荷尔蒙波动一致。在每一次访问中，都将收集有关饮食、体力活动和其他环境暴露的数据。尿样和血样将评估F2异前列腺素及其副产物、共轭双烷、空腹血糖、总胆固醇及其副产物以及血清抗氧化维生素的水平。 公共卫生意义：这项研究将阐明评估绝经前妇女氧化应激的最佳方法，并更好地了解氧化应激与月经功能的关系。这项研究还将为未来研究氧化应激在生育、自然流产风险和其他与妊娠相关的结局中的作用提供基本的参考数据。

As part of aerobic life, we oxidize a large pool of biomolecules to obtain chemical energy. During this process, several intermediates are formed; some are chemically unstable and are referred to as free radicals (FR). FR tend to react quickly with their surrounding biological environment; depending on the nature of the molecule attacked, different reactions can occur, i.e., lipid peroxidation, protein oxidation, or DNA oxidation products. As aerobic life has evolved, antioxidant defense systems against FR have developed. An imbalance between production of FR (oxidants) and defense systems against them (antioxidants) results in oxidative stress. This can lead to irreversible biochemical changes, with subsequent tissue damage and disease. Oxygen free radicals have been implicated in spontaneous abortions, infertility in men and women, reduced birth weight, aging and chronic disease processes, such as cardiovascular disease and cancer. While the mechanisms that relate oxidative stress with female fertility are not completely understood, recent animal and human studies have suggested that oxidative stress might have an important role in follicular growth, development of endometriosis, and regulation of angiogenesis in the endometrium. Micronutrient antioxidants, hormones and enzymatic antioxidants are able to neutralize oxygen free radicals and inhibit oxidation and, thereby, potentially reduce the risk of infertility. Numerous methods have been developed to measured lipid peroxidation products and lipid peroxidation damage in tissue, cell and body fluids. Markers of lipid peroxidation can be measured directly or by measuring any substance involved in the reaction process. Since radical species are the actual agents to injured cells, their direct measurement would be preferable for clinical diagnosis. However, radical species disappear rapidly yielding stable primary and secondary lipid peroxidation products. Although, lipid peroxidation has been related to many health outcomes, there still is large disagreement between investigators on which method should be use to evaluate circulating levels of lipid peroxidation making it difficult to synthesize research findings. Recently, it has been demonstrated that plasma lipoprotein levels fluctuate during the course of the menstrual cycle. This cyclic fluctuation in lipoproteins has been associated with fluctuation in plasma antioxidant concentrations . Hormones, lipoproteins, a-tocopherol and carotenoids were measured simultaneously for 2-3 consecutive days in each phase of the menstrual cycle for 12 healthy women. Carotenoids were lowest during menses, with concentrations of lutein/zeaxanthin and its metabolite, anhydrolutein, higher at all three phases (early follicular, late follicular and luteal) than during menses. Plasma -carotene peaked in the late follicular phase, whereas plasma lycopene, phytoene, phytofluene and retinol concentrations peaked in the luteal phase. Circulating levels of estradiol and progesterone have also been shown to fluctuate during the follicular and luteal phase of the menstrual cycle in ovulatory women. Estrogen is a powerful antioxidant that affects oxidative stress and homocysteine levels in women. However, little is known about the relation between oxidative stress, estrogen levels and their influence on outcomes such as likelihood of conception or spontaneous abortions. Prior to evaluating this relation, it is critical to have standardized measurements of oxidative stress and to know they vary with hormone levels. The primary goals of this study are to better understand the intricate relationship between hormone levels and oxidative stress during the menstrual cycle (i.e. estrogen, progesterone, LH, etc). More specifically, we would study: (i) the intra-cycle variation of oxidative stress; (ii) the relation between hormone levels and oxidative stress during the menstrual cycle in pre-menopauusal women; and (iii) influence of external factors such as cigarette smoking, alcohol consumption, and exercise on oxidative stress and hormone levels. Study Design: A prospective longitudinal cohort study of 250 women is being conducted in a university setting. Screening tests are performed on participating individuals to exclude women who are pregnant and or have asymptomatic chlamydia. The recruitment period will last up to one full calendar year to account for seasonal variability. The participants are being followed for 2 menstrual cycles from day 1 of the menstrual cycle to the end, taking blood and urine samples at intervals consistent with hormonal fluctuations. At each of these visits data will be collected on diet, physical activity and other environmental exposures. Urine and blood samples will be evaluated for levels of F2 isoprostanes and subproducts, conjugate dianes, fasting glucose, total cholesterol and subproducts, and serum antioxidant vitamins. Public Heath Significance: This study will elucidate the best methods to estimate oxidative stress in premenopausal women and to better understand the relation between oxidative stress and menstrual function. This study will also provide basic reference data for future studies examining the role of oxidative stress in fertility, risk of spontaneous abortion, and other pregnancy related outcomes.