Publications

2012
Audrey J Gaskins, Machelle Wilchesky, Sunni L Mumford, Brian W Whitcomb, Richard W Browne, Jean Wactawski-Wende, Neil J Perkins, and Enrique F Schisterman. 2012. “Endogenous reproductive hormones and C-reactive protein across the menstrual cycle: the BioCycle Study.” Am J Epidemiol, 175, 5, Pp. 423-31.Abstract
C-reactive protein (CRP) is one of the most commonly used markers of acute phase reaction in clinical settings and predictors of cardiovascular risk in healthy women; however, data on its physiologic regulation in premenopausal women are sparse. The objective of this study was to evaluate the association between endogenous reproductive hormones and CRP in the BioCycle Study (2005-2007). Women aged 18-44 years from western New York were followed prospectively for up to 2 menstrual cycles (n = 259). Serum levels of CRP, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to 8 times per cycle, timed by fertility monitors. CRP levels varied significantly across the cycle (P < 0.001). More women were classified as being at elevated risk of cardiovascular disease (CRP, >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%; P < 0.001). A 10-fold increase in estradiol was associated with a 24.3% decrease in CRP (95% confidence interval: 19.3, 29.0). A 10-fold increase in luteal progesterone was associated with a 19.4% increase in CRP (95% confidence interval: 8.4, 31.5). These results support the hypothesis that endogenous estradiol might have antiinflammatory effects and highlight the need for standardization of CRP measurement to menstrual cycle phase in reproductive-aged women.
Audrey J Gaskins, Sunni L Mumford, Jorge E Chavarro, Cuilin Zhang, Anna Z Pollack, Jean Wactawski-Wende, Neil J Perkins, and Enrique F Schisterman. 2012. “The impact of dietary folate intake on reproductive function in premenopausal women: a prospective cohort study.” PLoS One, 7, 9, Pp. e46276.Abstract
BACKGROUND: Folic acid is recommended to reproductive-aged women to prevent birth defects, though little is known about the effects of dietary intake on other reproductive outcomes. Improved pregnancy rates have been documented after folic acid supplement use, suggesting a possible link with ovulation, however research is limited. Our objective was to evaluate the association between dietary folate intake, hormone levels, and sporadic anovulation in healthy, regularly menstruating women. METHODOLOGY/PRINCIPAL FINDINGS: The BioCycle study (2005-2007) prospectively followed 259 healthy women aged 18-44 years from the western New York region for up to 2 menstrual cycles. Total folate and specific sources of folate were assessed up to 4 times per cycle by 24-hour recall. Estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured in serum up to 8 times per cycle, timed using fertility monitors. Anovulation was defined as a cycle with peak progesterone concentration ≤ 5 ng/mL and no LH peak in the mid/late luteal phase. Higher intake of dietary folate (in dietary equivalents) across tertiles had a marginally significant association with greater luteal progesterone levels (P trend 0.08). Higher intake of synthetic folate was significantly associated with higher luteal progesterone levels (P trend 0.05). Specifically, women in the 3(rd) tertile of synthetic folate intake had, on average, 16.0% (95% CI, 0.5-33.8%) higher luteal progesterone levels compared to women in the 1(st) tertile. Moreover, consumption of synthetic folate was significantly and inversely associated with anovulation such that women in the 3(rd) tertile had a 64% (95% CI, 8-86%) decreased odds of anovulation compared to the women in the 1(st) tertile (P trend 0.03). CONCLUSIONS/SIGNIFICANCE: These findings suggest that a diet high in synthetic folate may be associated with increased progesterone levels and lower risk of sporadic anovulation. Further study of the effect of dietary folate and folic acid supplement use on reproductive health is warranted.
Daniela S Colaci, Myriam Afeiche, Audrey J Gaskins, Diane L Wright, Thomas L Toth, Cigdem Tanrikut, Russ Hauser, and Jorge E Chavarro. 2012. “Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.” Fertil Steril, 98, 5, Pp. 1193-9.e1.Abstract
OBJECTIVE: To evaluate the association between men's body mass index (BMI), early embryo quality, and clinical outcomes in couples undergoing in vitro fertilization (IVF). DESIGN: Prospective cohort study. SETTING: Fertility clinic in an academic medical center. PATIENT(S): 114 couples who underwent 172 assisted reproduction cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fertilization rate, embryo quality, implantation rate, clinical pregnancy rate, and live birth rate. RESULT(S): The fertilization rate was higher among obese men than among normal weight men in conventional IVF cycles. No statistically significant associations were found between men's BMI and the proportion of poor-quality embryos on day 3, slow embryo cleavage rate, or accelerated embryo cleavage rate. Men's BMI was unrelated to positive β-human chorionic gonadotropin rate, clinical pregnancy rate, or live-birth rate per embryo transfer. Among couples undergoing intracytoplasmic sperm injection, the odds of live birth in couples with obese male partners was 84% lower than the odds in couples with men with normal BMI. CONCLUSION(S): Our data suggest a possible deleterious effect of male obesity on the odds of having a live birth among couples undergoing intracytoplasmic sperm injection.
2011
Sunni L Mumford, Enrique F Schisterman, Anna Maria Siega-Riz, Audrey J Gaskins, Anne Z Steiner, Julie L Daniels, Andrew F Olshan, Mary L Hediger, Kathleen Hovey, Jean Wactawski-Wende, Maurizio Trevisan, and Michael S Bloom. 2011. “Cholesterol, endocrine and metabolic disturbances in sporadic anovulatory women with regular menstruation.” Hum Reprod, 26, 2, Pp. 423-30.Abstract
BACKGROUND: Sporadic anovulation among regularly menstruating women is not well understood. It is hypothesized that cholesterol abnormalities may lead to hormone imbalances and incident anovulation. The objective was to evaluate the association between lipoprotein cholesterol levels and endocrine and metabolic disturbances and incident anovulation among ovulatory and anovulatory women reporting regular menstruation. METHODS: The BioCycle Study was a prospective cohort study conducted at the University at Buffalo from September 2005 to 2007, which followed 259 self-reported regularly menstruating women aged 18-44 years, for one or two complete menstrual cycles. Sporadic anovulation was assessed across two menstrual cycles. RESULTS: Mean total and low-density lipoprotein cholesterol and triglycerides levels across the menstrual cycles were higher during anovulatory cycles (mean difference: 4.6 (P = 0.01), 3.0 (P = 0.06) and 6.4 (P = 0.0002) mg/dl, respectively, adjusted for age and BMI). When multiple total cholesterol (TC) measures prior to expected ovulation were considered, we observed a slight increased risk of anovulation associated with increased levels of TC (odds ratio per 5 mg/dl increase, 1.07; 95% confidence interval, 0.99, 1.16). Sporadic anovulation was associated with an increased LH:FSH ratio (P = 0.002), current acne (P = 0.02) and decreased sex hormone-binding globulin levels (P = 0.005). CONCLUSIONS: These results do not support a strong association between lipoprotein cholesterol levels and sporadic anovulation. However, sporadic anovulation among regularly menstruating women is associated with endocrine disturbances which are typically observed in women with polycystic ovary syndrome.
Sunni L Mumford, Enrique F Schisterman, Anna Maria Siega-Riz, Audrey J Gaskins, Jean Wactawski-Wende, and Tyler J VanderWeele. 2011. “Effect of dietary fiber intake on lipoprotein cholesterol levels independent of estradiol in healthy premenopausal women.” Am J Epidemiol, 173, 2, Pp. 145-56.Abstract
High-fiber diets are associated with improved lipid profiles. However, pre- and postmenopausal women respond differently to fiber intake, suggesting that endogenous estradiol mediates the effect. The authors' objective was to determine the direct effect of fiber intake on lipoprotein cholesterol levels independent of estradiol among premenopausal women. The BioCycle Study, a prospective cohort study conducted at the State University of New York at Buffalo from 2005 to 2007, followed 259 healthy women for up to 2 complete menstrual cycles. Serum lipoprotein and hormone levels were measured at 16 visits timed using fertility monitors. Fiber intake was assessed by 8 24-hour recalls. Marginal structural models with inverse probability weights for both lipoprotein and estradiol levels were used to estimate controlled direct effects of the highest category of fiber intake (≥22 g/day vs. <22 g/day) while accounting for age, body mass index, total energy, vitamin E intake, physical activity, luteinizing hormone, follicle-stimulating hormone, and progesterone. Reductions were observed in total and low density lipoprotein cholesterol in women with higher fiber intakes. Direct effects were greater than total effects. These analyses suggested that estradiol mediates at least part of the association between fiber and cholesterol among premenopausal women. More research is needed to elucidate the biologic mechanisms driving these associations.
Sunni L Mumford, Enrique F Schisterman, Audrey J Gaskins, Anna Z Pollack, Neil J Perkins, Brian W Whitcomb, Aijun Ye, and Jean Wactawski-Wende. 2011. “Realignment and multiple imputation of longitudinal data: an application to menstrual cycle data.” Paediatr Perinat Epidemiol, 25, 5, Pp. 448-59.Abstract
Reproductive hormone levels are highly variable among premenopausal women during the menstrual cycle. Accurate timing of hormone measurement is essential, especially when investigating day- or phase-specific effects. The BioCycle Study used daily urine home fertility monitors to help detect the luteinising hormone (LH) surge in order to schedule visits with biologically relevant windows of hormonal variability. However, as the LH surge is brief and cycles vary in length, relevant hormonal changes may not align with scheduled visits even when fertility monitors are used. Using monitor data, measurements were reclassified according to biological phase of the menstrual cycle to more accurate cycle phase categories. Longitudinal multiple imputation methods were applied after reclassification if no visit occurred during a given menstrual cycle phase. Reclassified cycles had more clearly defined hormonal profiles, with higher mean peak hormones (up to 141%) and reduced variability (up to 71%). We demonstrate the importance of realigning visits to biologically relevant windows when assessing phase- or day-specific effects and the feasibility of applying longitudinal multiple imputation methods. Our method has applications in settings where missing data may occur over time, where daily blood sampling for hormonal measurements is not feasible, and in other areas where timing is essential.
2010
Audrey J Gaskins, Alisha J Rovner, Sunni L Mumford, Edwina Yeung, Richard W Browne, Maurizio Trevisan, Neil J Perkins, Jean Wactawski-Wende, and Enrique F Schisterman. 2010. “Adherence to a Mediterranean diet and plasma concentrations of lipid peroxidation in premenopausal women.” Am J Clin Nutr, 92, 6, Pp. 1461-7.Abstract
BACKGROUND: A Mediterranean diet has been associated with a reduced risk of cardiovascular disease and mortality. A possible mechanism is through a decrease in lipid peroxidation (LPO); however, evidence linking the Mediterranean diet with lower LPO in premenopausal women is sparse. OBJECTIVE: We investigated whether adherence to a Mediterranean diet was associated with lower LPO concentrations in premenopausal women. DESIGN: Two hundred fifty-nine healthy women aged 18-44 y were followed for ≤ 2 menstrual cycles. Plasma concentrations of F(2)-isoprostane (8-iso-PGF2α), 9-hydroxyoctadecadieneoic acid (9-HODE), and thiobarbituric acid reactive substances (TBARS) were measured ≤ 8 times per cycle at visits scheduled by using fertility monitors. Diet was assessed ≤ 4 times per cycle by using 24-h dietary recalls. The alternate Mediterranean Diet Score (aMED) (range: 0-9) was calculated on the basis of intake of vegetables, legumes, fruit, nuts, whole grains, red and processed meat, fish, and alcohol and the ratio of monounsaturated to saturated fat. RESULTS: A 1-unit increase in aMED was associated with a 4.50% decrease in 8-iso-PGF2α concentrations (95% CI: -6.32%, -2.65%) and a 14.01% decrease in 9-HODE concentrations (95% CI: -17.88%, -9.96%) after adjustment for energy intake, age, race, body mass index, plasma ascorbic acid, and serum cholesterol. No significant association was observed between aMED and TBARS. A 1-unit increase in aMED was associated with a 1.39% increase (95% CI: 0.07%, 2.72%) in plasma ascorbic acid concentrations. CONCLUSIONS: Adherence to a Mediterranean diet is associated with lower LPO and higher ascorbic acid concentrations. These results confirm that decreased LPO is a plausible mechanism linking a Mediterranean diet to reduced cardiovascular disease risk.
Enrique F Schisterman, Audrey J Gaskins, Sunni L Mumford, Richard W Browne, Edwina Yeung, Maurizio Trevisan, Mary Hediger, Cuilin Zhang, Neil J Perkins, Kathleen Hovey, and Jean Wactawski-Wende. 2010. “Influence of endogenous reproductive hormones on F2-isoprostane levels in premenopausal women: the BioCycle Study.” Am J Epidemiol, 172, 4, Pp. 430-9.Abstract
Endogenous reproductive hormones and oxidative stress have been independently linked to risk of chronic disease but mostly in postmenopausal women. The interplay between endogenous reproductive hormones and oxidative stress among premenopausal women, however, has yet to be clearly elucidated. The objective of this study was to investigate the association between endogenous reproductive hormones and F(2)-isoprostanes in the BioCycle Study. Women aged 18-44 years from western New York State were followed prospectively for up to 2 menstrual cycles (n = 259) during 2005-2007. Estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, F(2)-isoprostanes, and thiobarbituric acid-reactive substances were measured up to 8 times per cycle at clinic visits timed by using fertility monitors. F(2)-Isoprostane levels had an independent positive association with estradiol (beta = 0.02, 95% confidence interval: 0.01, 0.03) and inverse associations with sex hormone-binding globulin and follicle-stimulating hormone (beta = -0.04, 95% confidence interval: -0.07, -0.003; beta = -0.02, 95% confidence interval: -0.03, -0.002, respectively) after adjustment for age, race, age at menarche, gamma-tocopherol, beta-carotene, total cholesterol, and homocysteine by inverse probability weighting. Thiobarbituric acid-reactive substances, a less specific marker of oxidative stress, had similar associations. If F(2)-isoprostanes are specific markers of oxidative stress, these results call into question the commonly held hypothesis that endogenous estradiol reduces oxidative stress.
Sunni L Mumford, Enrique F Schisterman, Anna Maria Siega-Riz, Richard W Browne, Audrey J Gaskins, Maurizio Trevisan, Anne Z Steiner, Julie L Daniels, Cuilin Zhang, Neil J Perkins, and Jean Wactawski-Wende. 2010. “A longitudinal study of serum lipoproteins in relation to endogenous reproductive hormones during the menstrual cycle: findings from the BioCycle study.” J Clin Endocrinol Metab, 95, 9, Pp. E80-5.Abstract
CONTEXT: Exogenous estrogens have been shown to affect the lipid profile, leading to the hypothesis that endogenous estrogens may have similar effects. OBJECTIVE: The objective of the study was to evaluate the association between endogenous estrogen and serum lipoproteins across the menstrual cycle. DESIGN: This was a prospective cohort study. SETTING: The study was conducted at the University at Buffalo, 2005-2007. PARTICIPANTS: Participants included 259 healthy, regularly menstruating women aged 18-44 yr. MAIN OUTCOME MEASURES: Serum levels of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides measured up to eight times per cycle for up to two cycles were measured. RESULTS: Total and LDL cholesterol were lower during the luteal phase as compared with the follicular phase (P < 0.001), and HDL levels were highest around ovulation (P < 0.001). More women were classified above the desirable range (LDL > or =130 mg/dl or total cholesterol > or =200 mg/dl) when measured during the follicular phase. Estradiol was positively associated with HDL in acute effects models [beta = 0.019, 95% confidence interval (CI) 0.015, 0.022] and inversely associated with total (beta = -0.017, 95% CI -0.020, -0.014) and LDL cholesterol (beta = -0.023, 95% CI -0.027, -0.018) and triglycerides (beta = -0.041, 95% CI -0.054, -0.029) in persistent effects models. CONCLUSIONS: Endogenous estrogen, like exogenous estrogen, appears to have beneficial effects on the lipid profile. Because lipoprotein cholesterol levels vary across the menstrual cycle, cyclic variations in lipoprotein levels may need to be considered in the design and interpretation of studies in reproductive-age women and in the clinical management of women's cholesterol.
Audrey J Gaskins, Sunni L Mumford, Alisha J Rovner, Cuilin Zhang, Liwei Chen, Jean Wactawski-Wende, Neil J Perkins, and Enrique F Schisterman. 2010. “Whole grains are associated with serum concentrations of high sensitivity C-reactive protein among premenopausal women.” J Nutr, 140, 9, Pp. 1669-76.Abstract
In premenopausal women, elevated C-reactive protein (CRP) concentrations have been associated with an increased risk of negative reproductive outcomes. Whole grain consumption has been associated with lower CRP concentrations in older women; however, less is known about this relationship in younger women. We investigated whether whole grain intake was associated with serum high sensitivity CRP (hs-CRP) concentrations in young women. BioCycle was a prospective cohort study conducted at the University of Buffalo from 2005 to 2007, which followed 259 healthy women aged 18-44 y for or= 1 serving/d had 12.3% lower hs-CRP concentrations (P = 0.02) compared with nonconsumers. Women who consumed >or= 1 serving/d of whole grain had a lower probability of having moderate (P = 0.008) or elevated (P = 0.001) hs-CRP according to the AHA criteria compared with nonconsumers. Given that elevated concentrations of hs-CRP have been linked to adverse reproductive outcomes and pregnancy complications, interventions targeting whole grain consumption may have the potential to improve health status among young women.
2009
Audrey J Gaskins, Sunni L Mumford, Cuilin Zhang, Jean Wactawski-Wende, Kathleen M Hovey, Brian W Whitcomb, Penelope P Howards, Neil J Perkins, Edwina Yeung, and Enrique F Schisterman. 2009. “Effect of daily fiber intake on reproductive function: the BioCycle Study.” Am J Clin Nutr, 90, 4, Pp. 1061-9.Abstract
BACKGROUND: High-fiber diets have been associated with decreased breast cancer risk, likely mediated by the effect of fiber on lowering circulating estrogen concentrations. The influence of fiber on aspects of reproduction, which include ovulation, has not been well studied in premenopausal women. OBJECTIVE: The objective was to determine if fiber consumption is associated with hormone concentrations and incident anovulation in healthy, regularly menstruating women. DESIGN: The BioCycle Study was a prospective cohort study conducted from 2004 to 2006 that followed 250 women aged 18-44 y for 2 cycles. Dietary fiber consumption was assessed < or =4 times/cycle by using 24-h recall. Outcomes included concentrations of estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which were measured < or =8 times/cycle, and incident anovulation. RESULTS: Dietary fiber consumption was inversely associated with hormone concentrations (estradiol, progesterone, LH, and FSH; P < 0.05) and positively associated with the risk of anovulation (P = 0.003) by using random-effects models with adjustment for total calories, age, race, and vitamin E intake. Each 5-g/d increase in total fiber intake was associated with a 1.78-fold increased risk (95% CI: 1.11, 2.84) of an anovulatory cycle. The adjusted odds ratio of 5 g fruit fiber/d was 3.05 (95% CI: 1.07, 8.71). CONCLUSIONS: These findings suggest that a diet high in fiber is significantly associated with decreased hormone concentrations and a higher probability of anovulation. Further study of the effect of fiber on reproductive health and of the effect of these intakes in reproductive-aged women is warranted.
Audrey J Gaskins and Enrique F Schisterman. 2009. “The effect of lipid adjustment on the analysis of environmental contaminants and the outcome of human health risks.” Methods Mol Biol, 580, Pp. 371-81.Abstract
Past literature on exposure to lipophilic agents such as organochlorines (OCs) is conflicting, posing challenges for the interpretation of their potential human health risks. Since blood is often used as a proxy for adipose tissue, it is necessary to model serum lipids when assessing health risks of OCs. Using a simulation study, we evaluated four statistical models (unadjusted, standardized, adjusted, and two-stage) for the analysis of polychlorinated biphenyls (PCBs) exposure, serum lipids, and health outcome risk. Eight candidate true causal scenarios, depicted by directed acyclic graphs, were used to illustrate the ramifications of misspecification of underlying assumptions when interpreting results. Biased results were produced when statistical models that deviated from the underlying causal assumptions were used with the lipid standardization method found to be particularly prone to bias. We concluded that investigators must consider biology, biological medium, laboratory measurement, and other underlying modeling assumptions when devising a statistical model for assessing health outcomes in relation to environmental exposures.
Enrique F Schisterman, Audrey J Gaskins, and Brian W Whitcomb. 2009. “Effects of low-dose aspirin in in-vitro fertilization.” Curr Opin Obstet Gynecol, 21, 3, Pp. 275-8.Abstract
PURPOSE OF REVIEW: In theory, use of aspirin in IVF is based on its anti-inflammatory, vasodilatory, and platelet aggregation inhibition properties, which improve blood flow to a woman's implantation site. It is hypothesized that this effect on blood flow will improve success rates. RECENT FINDINGS: Clinical studies investigating the use of low-dose aspirin (LDA) as an adjuvant therapy to IVF have produced conflicting results. The conflicting results have come as a consequence of the heterogeneous mixture of clinical trials with lack of adequate power. Even after multiple meta-analyses, differing estimates of effect were calculated as to whether aspirin should be used in conjunction with IVF. SUMMARY: Conflicting results leave the question of the effects of LDA in IVF unanswered. More trials are required for analysis to have adequate statistical power and until then the data remain unclear. At this point, there are not enough data to show that aspirin has a beneficial effect on the outcomes of IVF, but absence of effect is not adequate grounds to overturn the current clinical practice for those using LDA in efforts aimed at achieving success with IVF.

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