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The Journal of Nutrition Vol. 128 No. 7 July 1998,
pp. 1150-1155
-Tocopherol Concentrations in Plasma but not in Lipoproteins Fluctuate during the Menstrual Cycle in Healthy Premenopausal Women1
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Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD; * The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA; Lipid Research Clinic Laboratory, Department of Medicine, George Washington University Medical Center, Washington, DC; and ** Beltsville Human Nutrition Research Center, Agricultural Research Service, USDA, Beltsville, MD
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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Because premenopausal women experience cyclic fluctuations of plasma carotenoids and their lipoprotein carriers, it was hypothesized that plasma 
-tocopherol (A-T) fluctuates by phase of the menstrual cycle. Twelve free-living women, with a confirmed ovulatory cycle, were given a controlled diet for two consecutive menstrual cycles. Blood was drawn during the menses, early follicular, late follicular and luteal phases to simultaneously measure serum hormones, plasma lipoproteins and A-T concentrations, and A-T distribution in the lipoprotein fractions. Plasma A-T concentrations were significantly lower during menses than during the luteal phase by ~12% in each controlled diet cycle (P < 0.001). Adjustment for serum cholesterol and triglyceride concentrations did not alter these findings. The distributions of A-T in lipoprotein cholesterol fractions were not significantly different by menstrual phase. From 61 to 62% of A-T was concentrated in the LDL fraction, with another 9-14% in HDL2, 17-22% in HDL3 and the remaining 6-8% in VLDL+ IDL. There were no significant differences in lipoprotein cholesterol fractions by menstrual phase, except for a significant increase (P = 0.03) in HDL2 cholesterol from the early follicular to the late follicular phase. Spearman rank correlations from data during the second controlled diet month showed A-T in HDL2 in the late follicular phase was positively correlated with HDL cholesterol in the early follicular (r = 0.88), late follicular (r = 0.86) and luteal phases (r = 0.86) and with luteal apolipoprotein (ApoA-1) level (r = 0.90), and luteal HDL2 cholesterol (r = 0.83). A-T in HDL3 in the early follicular phase was negatively correlated with HDL2 cholesterol (r = 
0.96) and ApoA-1 (r = 0.85), whereas luteal A-T in HDL3 was correlated with luteal HDL3 cholesterol (r = 0.79). Late follicular A-T in VLDL was positively correlated with early follicular HDL3 cholesterol and late follicular HDL3 cholesterol (r = 0.83). Fluctuations of A-T concentrations by phase of the menstrual cycle should be taken into consideration in future research concerning premenopausal women and the risk of chronic disease.
In the past few years, there has been a resurgence of interest in the role of antioxidants and in coronary artery disease. From an interim analysis of 16 of 33 populations participating in the WHO study to monitor trends and determinants in cardiovascular disease, there was a strong inverse correlation between lipid standardized vitamin E concentrations and risk of coronary artery disease mortality across the study communities (Gey et al. 1991 Although vitamin E occurs in nature in eight different forms, Female volunteers were recruited from the Beltsville, MD area. After an initial screening by phone, potential participants visited the National Institutes of Health (NIH) Clinical Center for a physical and gynecologic exam, blood biochemistries and an in-person interview (Forman et al. 1996
Study design.
The study was designed as a free-living (FL) study of one menstrual cycle to confirm ovulation followed by a controlled diet study for two consecutive menstrual cycles (Forman et al. 1996 Measurement of serum hormones, plasma lipids, and Statistical analysis.
In the initial analysis, measures of central tendency for plasma concentrations of A-T, total cholesterol, LDL-C and HDL-C were calculated for each phase (menses, early follicular, late follicular and luteal) of the menstrual cycle and each of the following diet cycles: FL, free-living menstrual cycle; CD1, first controlled diet menstrual cycle; and CD2, second controlled diet menstrual cycle. Plasma A-T concentrations of each subject were averaged over 2-3 consecutive days during the menses, early follicular and luteal phases, respectively. In the late follicular phase, measurements on the two menses days before plus the day of the LH surge were averaged to estimate plasma A-T concentrations. Daily plasma lipoprotein concentrations were matched with plasma A-T concentrations by phase of the menstrual cycle.
There were no significant differences in plasma A-T by menstrual cycle phase during the free-living time (Table 2). In CD1, A-T was lower at menses than during the early follicular (P = 0.0001), late follicular (P = 0.0001) or luteal (P = 0.0002) phases. In CD2, A-T was higher in the luteal phase than in the early follicular phase (P = 0.004), late follicular phase (P = 0.008) or during menses (P = 0.0001). During both controlled diet months, plasma A-T during menses was ~12% lower than during the luteal phase (P = 0.002, CD1 and P = 0.0001, CD2). Adjustment of plasma A-T for plasma total cholesterol and triglyceride concentrations did not alter the results (Table 2).
The purpose of this investigation was to determine whether A-T levels fluctuate by phase of the menstrual cycle in healthy premenopausal women. Because diet can alter both plasma A-T and lipoprotein levels and thus obscure any true differences, this study was conducted under controlled dietary conditions. In both controlled diet cycles, CD1 and CD2, plasma A-T concentrations were 12% lower during menses than during the luteal phase (P = 0.0002, P = 0.0001). Thus this is the first study to report on the menstrual periodicity of circulating A-T under controlled dietary conditions.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
). It has been postulated that vitamin E protects against coronary artery disease through its ability to inhibit the formation of oxidized LDL, which possesses pro-atherogenic properties (Steinberg et al. 1989). Furthermore, the vitamin E concentration in the LDL was inversely associated with the development of stenoses in coronary arteries; thus a reduced ratio of vitamin E/LDL may contribute to clinically manifest coronary artery disease (Regnstrom et al. 1995). Results from other observational epidemiologic studies on cardiovascular disease risk and plasma vitamin E levels are not totally consistent (Manson et al. 1993). The relationship of plasma vitamin E and specific cancers is even more controversial (Flagg et al. 1995). These inconsistent findings could be due to normal variation in plasma levels of vitamin E as well as the range in concentration of vitamin E in the various lipoproteins. Understanding the determinants of distribution of vitamin E in the lipoproteins and how this distribution relates to total plasma levels of vitamin E may lead to a better understanding of how vitamin E protects LDL from oxidation and the potential role of vitamin E in cell proliferation and signal transduction (Traber and Packer 1995).
-tocopherol (A-T)3 is the form found in highest concentrations in human plasma and tissue and has the highest biological activity (Kayden and Traber 1993). A-T is transported in lipoproteins (McCormick et al. 1960). Recently, it has been demonstrated that plasma lipoprotein levels fluctuate by phase of the menstrual cycle (Cohn et al. 1992). This cyclic fluctuation in lipoproteins could be associated with fluctuation in plasma antioxidant concentrations. As part of a controlled feeding study of the fluctuation of plasma lipoproteins and serum hormones by phase of the menstrual cycle, plasma carotenoids and A-T were examined. Hormones, lipoproteins, A-T and carotenoids were measured simultaneously for 2-3 consecutive days of each phase of the menstrual cycle. The fluctuations in plasma lipoprotein and carotenoid concentrations were recently published (Forman et al. 1996, Muesing et al. 1996). LDL cholesterol (LDL-C) levels were lowest during the luteal phase, HDL-C levels were highest at the late follicular phase, and ApoA-l levels were highest during the luteal phase (Muesing et al. 1996). 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 (Forman et al. 1996). Plasma 
-carotene peaked at the late follicular phase, whereas plasma lycopene, phytoene, phytofluene and retinol concentrations peaked at the luteal phase (Forman et al. 1996). The objective of this paper is to report the cyclic fluctuations of -tocopherol, the major circulating form of vitamin E, and the distribution of -tocopherol in lipoproteins by phase of the menstrual cycle during a controlled dietary study.
SUBJECTS AND METHODS
Abstract
Introduction
Methods
Results
Discussion
References
). Participants met the following eligibility criteria: 1) aged 20-34 y; 2) non-smokers; 3) not pregnant, not receiving hormone preparations or breast feeding in the past 6 mo; 4) no history or clinical signs of gynecologic problems; 5) within 20% of weight for height based on age and gender-specific reference values; 6) plasma cholesterol, triglyceride and hemoglobin concentrations within the normal range for women of reproductive age; 7) not consuming a restricted diet or a regular user of vitamin-mineral supplements; and 8) willingness to stop supplementation and to abstain from alcohol use during the controlled diet study. The protocol was approved by the internal review boards of the George Washington University School of Medicine, the National Cancer Institute and the Beltsville Human Nutrition Research Center (BHNRC), USDA.
). Three others were removed from the analysis of the distribution of A-T in lipoproteins because their lipoprotein fractions were stored inappropriately (4°C). Thus data were available to describe plasma fluctuations of A-T in 12 women and the A-T distribution in lipoproteins in 9 of these 12 women. There were no significant differences in major characteristics of these two groups of women (Table 1).
View this table:
Table 1.
Characteristics of the study participants1
). The diet study was conducted at the BHNRC, USDA. Each woman began the free-living study on her first menses day. Food and beverage records were kept during this menstrual cycle. The controlled diet study consisted of a 7-d repeat menu cycle. The daily diet was composed of 36% of energy from fat (polyunsaturated:saturated ratio of 0.53), 19% from protein, 55% from carbohydrates and 3.4 g of fiber/100 kJ. The dietary intake of vitamin E during the two controlled diet periods was 8.1 ± 1.1 mg tocopherol equivalents (TE). Dietary intake of vitamin E in the FL month was 8.2 ± 5.2 mg for all twelve women and 8.8 ± 4.9 mg TE for the nine women.
-tocopherol on the lipoprotein fractions.
Blood samples were collected between 0600 and 0700 h from women who had fasted for >12 h. Samples were collected in EDTA and non-EDTA glass vacutainers for plasma A-T/lipoprotein and serum hormone analyses, respectively. Blood drawing for plasma concentrations of lipoproteins and A-T occurred on the following days of the menstrual cycle: 1) menses, menses d 1 and 2; 2) early follicular, menses d 4-6; 3) late follicular, menses d 11 through 1 d after serum luteinizing hormone (LH) concentration was >30 mIU/L, and 4) midluteal, menses d 7-8 post-LH surge. An ovulatory cycle was defined as a serum LH concentration 
30 U/L at the time of LH surge and a serum progesterone concentration 13 nmol/L at the midluteal phase.
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and Muesing et al. (1992). Very low plus intermediate density lipoproteins (VLDL + IDL) and LDL + HDL fractions were isolated by preparative ultracentrifugation (100,000 × g for 18 min at 10°C) at a density of 1.019 kg/L, thus avoiding the confounding of the IDL contribution to the LDL and HDL fractions. Cholesterol and triglycerides were determined enzymatically (Hainline et al. 1974). LDL concentration was the difference between (HDL + LDL) minus HDL; HDL2 concentration was the difference between the HDL and HDL3 concentrations. The plasma and isolated fractions were stored frozen at 80°C, and then all samples from an individual were analyzed sequentially as a set. The laboratory maintains standardization with the Centers for Disease Control and Prevention for analysis of cholesterol, triglycerides and HDL-C.
and Ribaya-Mercando et al. (1995).
HDL3)] by phase of the last cycle. An adjustment for VLDL + IDL and LDL A-T concentrations was added to the model to correct for the differences in the sum of the lipoprotein A-T concentrations in contrast with the actual plasma A-T concentrations. The sum of the lipoprotein concentrations ranged from 97 to 101% of the plasma concentrations. The percentage of A-T in each lipoprotein was calculated by summing the least square mean values for A-T in VLDL + IDL, LDL, HDL2 and HDL3, then dividing A-T in a specific lipoprotein fraction by the sum and multiplying by 100. All differences were considered significant when the two-sided P-value was < 0.05.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
View this table:
Table 2.
Concentrations of plasma -tocopherol in women by phase of the menstrual cycle during free-living (FL)
and controlled dietary (CD) conditions
View this table:
Table 3.
Concentration and distribution of -tocopherol in premenopausal women's plasma lipoprotein fractions during the early follicular, late follicular and luteal phases of the menstrual cycle in the second month of a controlled diet
View this table:
Table 4.
Spearman rank correlation coefficients between -tocopherol (A-T) concentration in the lipoprotein fractions
and lipoprotein cholesterol (C) concentrations in the early follicular, late follicular and luteal phases
of the menstrual cycle during the second month of a controlled diet1
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
found no fluctuations in plasma A-T under free-living conditions. Our results in the FL month are in agreement with these findings. Although dietary vitamin E intake was similar (~8.1 mg TE) during all three menstrual cycles (FL, CD1 and CD2), the higher level of variation in the FL month [SD = 5.2 mg TE (FL) vs. 1.1 mg TE (CD2)] could have reduced the chances of seeing any differences. The lower amount of circulating A-T during menses (~12%) compared with the luteal phase was found in both CD cycles. The slight increase in A-T in the luteal phase of the second month of controlled feeding could be due to the sustained increase in carotenoid-rich foods. Several studies have shown that an increase in carotenoid intake leads to an increase in serum tocopherol level (Fontham et al. 1995, Goodman et al. 1994). The higher level of circulating A-T in the luteal phase compared with during menses mimics the recently reported findings in plasma carotenoid and suggests that levels of available circulating micronutrients might be reduced during menses along with the lower immune status during this time (Forman et al. 1996). Because cyclic fluctuations in lipoproteins could be responsible for the observed differences in A-T, we also adjusted all data for plasma total cholesterol and triglyceride levels. These adjustments did not alter the findings.
). Thus, the body expends considerable effort to maintain concentrations of A-T in the plasma for delivery to tissues (Cohn et al. 1992). Little is known about the regulation and transfer of A-T between plasma and tissue. Recent studies in rats revealed that ovarian levels of A-T increased during the luteal phase after steriogenesis. Therefore, the antioxidant reserve of the ovary may be in a dynamic state that is under endocrine regulation (Aten et al. 1994). Our finding of the highest concentration of plasma A-T during the luteal phase might be similar to the findings of Aten et al. and reflects A-T transfer from either the ovary or other hormone-dependent tissue; however, this interpretation requires further investigation. Of course, there are physical collisions between lipoprotein particles, which could lead to some exchange of A-T between lipoproteins in plasma.
reported a significant difference in distribution between men and women. Men carried more A-T in LDL than HDL, whereas the opposite was true for women. It has been suggested that the difference might be explained by differences in lipoprotein levels between men and women. Since that publication in 1982, there have been six studies reporting distribution of A-T among lipoprotein fractions. Data for women alone were reported in four of these (Carelain et al 1992, Clevidence et al 1989, Kostner et al 1996, Ogiharo et al 1988, Ribaya-Mercada et al. 1995, and Romanchik et al. 1995). In two studies, 50-53% of A-T was concentrated in the HDL fractions and 41-47% was found in the LDL fraction (Carelain et al. 1992, Ogiharo et al. 1988). In the remaining two studies, a higher percentage of A-T was found in the LDL than the HDL fraction, similar to the percentages in males (Clevidence et al. 1989, Ribaya-Mercada et al 1995). These differences may be due to factors such as methodological procedures and/or differences in recoveries of lipoprotein fractions. Moreover, recent studies have shown a relatively higher proportion of A-T in the VLDL fraction, ranging from 21 to 25% compared with the 6-8% found in this study (Kostner et al. 1996, Ribaya-Mercado et al. 1995, Romanchik et al. 1995). The higher percentage could be due to the higher amount of VLDL-C present in plasma in postmenopausal women and men in previous studies in contrast with the lower levels of triglycerides and hence VLDL-C in the premenopausal women of this study.
found that HDL2a-C levels increase during the luteal phase. In that study, women did not consume a controlled diet and the menstrual cycle was determined by calendar days rather than serum hormone measurement. This latter factor could contribute to some imprecision in the estimate of phase-specific HDL-C levels. The findings in our study and that of Williams et al. are consistent with the observations that postmenopausal estrogen replacement therapy increases HDL2-C and that coronary heart disease risk may be increased when HDL2 is decreased relative to HDL3-C (Johansson et al. 1991, Williams et al. 1993).
). A-T in HDL correlated highly with the amount of protein in HDL, but A-T in LDL was not associated with LDL protein (Behrens 1982). In the other study, A-T in HDL was positively correlated with ApoA and HDL-C (Clevidence and Lehmann 1989). Total serum A-T was also correlated with serum ApoA-1 and HDL-C, but not serum ApoB and LDL + VLDL-C. In contrast, a recent study in postmenopausal women found that A-T in HDL was not correlated with HDL-C, but A-T in LDL was positively correlated with LDL-C, and A-T in VLDL was positively correlated with VLDL-C (Ribaya-Mercada 1995). Traber et al. (1992) described a positive correlation between the HDL protein, ApoA-1, and the amount of A-T in HDL and suggested that A-T associates with the protein moiety of HDL. Ziouzenkova et al. (1996) found A-T to be positively correlated with total plasma cholesterol, but not A-T in LDL. Clearly, more research is required on the physiologic importance of this observation to understand what factors control the distribution of A-T in the lipoproteins.
). Furthermore, the magnitude of the changes for these antioxidants is larger than the cyclic fluctuation of lipoprotein cholesterol. The distribution of A-T in the lipoprotein cholesterol fractions [VLDL (6-8%), LDL (61-62%), HDL2 (9-14%) and HDL3 (17-22%)] is quite similar to the pattern for lutein and differs from the distribution for the hydrocarbon carotenoids, which are more concentrated in LDL (Forman et al. 1997). As with studies of lipids and carotenoids, studies of A-T in premenopausal women require consideration of menstrual periodicity. Our findings suggest the need for more studies in women to investigate the distribution of A-T in the HDL subclasses, especially because these subclasses appear to be influenced by hormone levels.
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FOOTNOTES |
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-tocopherol; CD1, first month of controlled diet feeding; CD2, second month of controlled diet feeding; FL, free-living (no controlled diet); HDL cholesterol, HDL-C; LDL cholesterol, LDL-C; LH, luteinizing hormone; TE, tocopherol equivalents.
Manuscript received 21 November 1997. Initial reviews completed 12 December 1997. Revision accepted 27 March 1998.
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LITERATURE CITED |
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Abstract
Introduction
Methods
Results
Discussion
References
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-tocopherol in human plasma lipoproteins.
Am. J. Clin. Nutr.
1982;
35:691-696- carotene supplementation on serum -tocopherol concentration.
Epidemiol. Biomarkers Prev.
1995;
4:801-803 -carotene and vitamin A administration on serum concentrations of -tocopherol.
Cancer Epidemiol. Biomarkers & Prev.
1994;
3:429-432[Abstract] -tocopherol between lipoproteins and cells.
Biochem. J.
1996;
305:659-667 -carotene supplementation on the concentrations and distributions of carotenoid, vitamin E, vitamin A, and cholesterol in plasma lipoprotein and non-lipo-protein fractions in healthy older women.
J. Am. Coll. Nutr.
1995;
14:614-620[Abstract] -tocopherol among lipoproteins do not change when human plasma is incubated in vitro.
J. Nutr.
1995;
125:2610-2617 This article has been cited by other articles:
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