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EB Research - Reproductive Epidemiology
The BioCycle Study: A Longitudinal Study of the Estrogen and Progesterone Effects on Biomarkers of Oxidative Stress and Antioxidant Status During the Menstrual Cycle
The BioCycle Study is a prospective cohort study completed at the University at Buffalo and offers a unique and comprehensive assessment of menstrual cycle function. The primary goal of the BioCycle Study was to better understand the intricate relationship between hormone levels and oxidative stress during the menstrual cycle (i.e., estrogen, progesterone, luteinizing hormone, etc.). Multiple markers of oxidative stress, reproductive hormones, inflammation, and metabolic biomarkers were measured in a cohort of 259 women of reproductive age over the course of two menstrual cycles. Fertility monitors were utilized to time the subjects' visits to ensure appropriate timing of biospecimen collection. This allowed visits to be specific to each individual's menstrual cycle, accounting for differences in the timing of menstrual cycle phases across women. Additional information was obtained throughout the study regarding lifestyle, diet, bone density, body hair patterns, and acne. Overall, compliance to the protocol was high; 87% of women attended at least 7 visits out of a possible 8.
Important Research Findings
Since completion of the study much progress has been made in the analysis of the BioCycle Study. With regards to the main question under study, we found a significant positive association between F2-Isoprostanes (a marker of oxidative stress) and estrogen which calls into question the hypothesis of estrogen serving as an antioxidant. We have also shown that metabolic markers such as oxidative stress, lipoprotein cholesterol, inflammation, glucose metabolism, and uric acid vary significantly across the menstrual cycle among healthy regularly cycling women. While absolute changes were generally modest, we observed that women passed between clinically relevant risk categories depending on which phase of the menstrual cycle biomarkers were measured. The hypothesized cardioprotective effects of estrogen in premenopausal women may actually be partially explained by hormonal variability. While the best time to measure biomarkers during a woman’s cycle has yet to be established, measurements should be made during the same cycle phase for consistent comparisons. Further, biomarker variability was observed among healthy women, and it is possible that other populations have even greater variability. These results have implications for clinical practice (i.e., doctor visits should be timed to menstrual cycle phase) and for study designs among women of reproductive age.
The BioCycle Study is the first to report that fiber intakes above the recommended levels were associated with an increased risk of anovulation, highlighting a perhaps unintended consequence of high fiber intakes. These findings are of great interest to reproductive age women trying to conceive and deserve further study. Knowing the complex relationships between fiber intake and reproductive hormone levels, this work was extended to evaluate the impact of a high fiber diet on cholesterol levels while accounting for changing estradiol levels. We found that the effects of dietary fiber intake on lowering cholesterol varied by estrogen level. That is, at high levels of estrogen, high fiber diets modified cholesterol levels less than at lower estrogen levels. Not only is this work of great interest due to its implications for nutritional epidemiology in understanding the possible differences in the effects of a high fiber diet for premenopausal and postmenopausal women and men, but represents an application of newly developed analysis techniques to answer questions related to mediation.
The BioCycle Study has also offered valuable insights into the benefits of a healthy diet for young premenopausal women. For example, we have evaluated the importance of eating whole grains in reducing levels of high sensitivity C-reactive protein, a marker of inflammation and future disease risk. Adherence to a Mediterranean diet was also observed to be associated with decreased levels of lipid peroxidation, and caffeine intake was associated with estradiol levels. Each of these papers has been influential in describing the impact of a healthy diet on hormonal function and ovulation, and in linking previous research regarding the effects of a healthy diet on later chronic disease outcomes among reproductive age women.
The BioCycle team intends to continue analyzing data resulting from this study to answer important public health questions for women of reproductive age. The study design of BioCycle provides a unique opportunity to evaluate the influence of multiple factors on menstrual cycle measures and variability. Planned analyses will target lifestyle, behavior and other factors in relation to various measures of menstrual cycle function.
Biospecimens from the cohort have been used as the basis of an ancillary study of caffeine, anti-müllerian hormone, inhibin B, folate, testosterone, and leptin levels during the menstrual cycle. For this study, serum specimens were selected to be analyzed to help characterize levels longitudinally, as well as evaluate correlates with measures of ovarian function and risk factors. Laboratory analysis will be completed in 2012. These ancillary studies were led by Drs. Sunni Mumford, Karen Schliep, and Anna Pollack.
- Katherine Ahrens, Ph.D.
- Paul Albert, Ph.D.
- Kerri Kissell, M.D.
- Pauline Mendola, Ph.D.
- Sunni L. Mumford, Ph.D.
- Neil Perkins, Ph.D..
- Anna Pollack, Ph.D., M.P.H.
- Ankita Prasad, B.A.
- Karen Schliep, Ph.D., M.S.P.H.
- Edwina Yeung, Ph.D.
- Cuilin Zhang, M.D., M.P.H., Ph.D.
- Wactawski-Wende J, Schisterman EF, Hovey K, Howards PP, Browne RW, Hediger M, Liu A, & Trevisan M. (2009). BioCycle study: design of the longitudinal study of the oxidative stress and hormone variation during the menstrual cycle. Paediatr Perinat Epidemiol, 23(2), 171-184. PMID: 19159403
- Howards PP, Schisterman EF, Wactawski-Wende J, Reschke JE, Frazer AA, & Hovey KM. (2009). Timing clinic visits to phases of the menstrual cycle by using a fertility monitor: the BioCycle Study. American Journal of Epidemiology, 169(1), 105-112. PMID: 18974081
- Gaskins AJ, Mumford SL, Zhang C, Wactawski-Wende J, Hovey KM, Whitcomb BW, Howards PP, Perkins NJ, Yeung E, & Schisterman EF. (2009). Effect of daily fiber intake on reproductive function: the BioCycle Study. American Journal of Clinical Nutrition, 90(4), 1061-1069. PMID: 19692496
- Schisterman EF, Gaskins AJ, Mumford SL, Browne RW, Yeung E, Trevisan M, Hediger M, Zhang C, Perkins NJ, Hovey K, Wactawski-Wende J; for the BioCycle Study Group. (2010). Influence of endogenous reproductive hormones on F2-Isoprostane levels in premenopausal women: the BioCycle Study. American Journal of Epidemiology, 172(4), 430-439. PMID: 20679069
- Mumford SL, Schisterman EF, Siega-Riz AM, Browne RW, Gaskins AJ, Trevisan M, Steiner AZ, Daniels JL, Zhang C, Perkins NJ, & Wactawski-Wende J. (2010). A longitudinal study of serum lipoproteins in relation to endogenous reproductive hormones during the menstrual cycle: findings from the BioCycle study. Journal of Clinical Endocrinology and Metabolism, 95(9), e80-85. PMID: 20534764
- Yeung EH, Zhang C, Mumford SL, Ye A, Trevisan M, Chen L, Browne RW, Wactawski-Wende J, Schisterman EF. (2010). Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: The BioCycle Study. Journal of Clinical Endocrinology and Metabolism, 95(12), 5435-5442. PMID: 20843950
- Mumford SL, Schisterman EF, Siega-Riz AM, Gaskins AJ, Steiner AZ, Daniels JL, Olshan AF, Hediger ML, Hovey KM, Wactawski-Wende J, Trevisan M, Bloom MS. (2011). Cholesterol, endocrine and metabolic disturbances in sporadic anovulatory women with regular menstruation. Human Reproduction, 26(2), 423-430. PMID: 21115506
- Pollack AZ, Schisterman EF, Goldman LR, Mumford SL, Albert PS, Jones RL, Wactawski-Wende J. (2011). Cadmium, lead, and mercury in relation to reproductive hormones and anovulation in premenopausal women. Environmental Health Perspectives, 119(8), 1156-1161. PMID: 21543284
- Gaskins AJ, Wilchesky M, Mumford SL, Wactawski-Wende J, Perkins NJ, Schisterman EF. (2012). Endogenous reproductive hormones and C-reactive protein across the menstrual cycle: the BioCycle study. American Journal of Epidemiology, 175(5), 423-431. PMID: 22306563
- Dasharathy S, Mumford SL, Pollack AZ, Perkins NJ, Mattison D, Wactawski-Wende J, Schisterman EF. (2012). Menstrual bleeding patterns among regularly menstruating women. American Journal of Epidemiology, 175(6), 536-545. PMID: 22350580
- Pollack AZ, Schisterman EF, Goldman LR, Mumford SL, Wactawski-Wende J. (2012). Relation of blood cadmium, lead, and mercury levels to biomarkers of lipid peroxidation in premenopausal women. American Journal of Epidemiology, 175(7), 645-652. PMID: 22302120
- Schliep K, Schisterman EF, Mumford SL, Pollack AZ, Zhang C, Ye A, Stanford JB, Hommoud AO, Porucznik CA, Wactawski-Wende J. (2012). Caffeinated beverage intake and reproductive hormones among premenopausal women in the BioCycle Study. American Journal of Clinical Nutrition, 95(2), 488-497. PMID: 22237060