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以获得化学能。在这个过程中，形成了几种中间体;一些是化学不稳定的，被称为自由基（FR）。FR倾向于与周围的生物环境快速反应;根据被攻击分子的性质，可能发生不同的反应，即，脂质过氧化、蛋白质氧化或DNA氧化产物。随着有氧生活的发展，针对FR的抗氧化防御系统也得到了发展。FR（氧化剂）和防御系统（抗氧化剂）之间的不平衡导致氧化应激。这可能导致不可逆的生化变化，随后的组织损伤和疾病。 氧自由基与自然流产、男女不育、出生体重减轻、衰老和心血管疾病和癌症等慢性疾病过程有关。尽管氧化应激与女性生育力的相关机制尚未完全了解，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展和子宫内膜血管生成的调节中起重要作用。营养素抗氧化剂、激素和酶抗氧化剂能够中和氧自由基并抑制氧化，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或通过测量反应过程中涉及的任何物质来测量。由于自由基物质是损伤细胞的实际代理人，它们的直接测量将是最好的临床诊断。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。虽然，脂质过氧化已与许多健康结果，仍然有很大的分歧，研究人员之间的方法应该使用，以评估循环水平的脂质过氧化，使其难以综合的研究结果。 最近，已经证明血浆脂蛋白水平在月经周期过程中波动。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。对12名健康妇女在月经周期各期连续2-3天同时测定激素、脂蛋白、α-生育酚和类胡萝卜素。类胡萝卜素在月经期间最低，叶黄素/玉米黄质及其代谢产物，脱水叶黄素的浓度在所有三个阶段（早期卵泡，晚期卵泡和黄体）高于月经期间。血浆胡萝卜素在卵泡后期达到峰值，而血浆番茄红素、八氢番茄红素、六氢番茄红素和视黄醇浓度在黄体期达到峰值。 循环中雌二醇和孕酮的水平也被证明在排卵妇女月经周期的卵泡期和黄体期波动。雌激素是一种强大的抗氧化剂，影响女性的氧化应激和同型半胱氨酸水平。然而，很少有人知道氧化应激，雌激素水平和它们对结果的影响，如怀孕或自然流产的可能性之间的关系。 在评估这种关系之前，至关重要的是要有标准化的氧化应激测量，并知道它们随激素水平而变化。 这项研究的主要目的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，LH等）之间的复杂关系。更具体地说，我们将研究：（一）氧化应激的周期内变化;（二）激素水平和氧化应激之间的关系，在月经周期的pre-autusal妇女;和（iii）外部因素的影响，如吸烟，饮酒，和运动对氧化应激和激素水平。 研究设计：一项前瞻性纵向队列研究，250名妇女正在进行的大学设置。对参与者进行筛查测试，以排除怀孕和/或无症状衣原体感染的妇女。招聘期将持续一个完整的日历年，以考虑季节性变化。从月经周期的第1天到结束，参与者被跟踪2个月经周期，以与激素波动一致的间隔采集血液和尿液样本。在每次访视时，将收集有关饮食、体力活动和其他环境暴露的数据。 将评价尿液和血液样本的F2异前列腺素和亚产物、共轭二烷、空腹血糖、总胆固醇和亚产物以及血清抗氧化维生素水平。 公共卫生意义：这项研究将阐明最好的方法来估计氧化应激在绝经前妇女和更好地了解氧化应激和月经功能之间的关系。这项研究也将为未来的研究提供基本的参考数据，研究氧化应激在生育，自然流产风险和其他妊娠相关结果中的作用。

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.