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.

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Schliep, Karen C; Schisterman, Enrique F; Wactawski-Wende, Jean et al. (2016) Serum caffeine and paraxanthine concentrations and menstrual cycle function: correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study. Am J Clin Nutr 104:155-63
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Matyas, R A; Mumford, S L; Schliep, K C et al. (2015) Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women. Hum Reprod 30:1714-23

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