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Plasma Selenium and Plasma and Erythrocyte Glutathione Peroxidase Activity Increase with Estrogen during the Menstrual Cycle

Department of Human Nutrition, The Ohio State University, Columbus, Ohio

Address reprint requests to: Anne M. Smith, Ph.D., R.D., 325 Campbell Hall, Department of Human Nutrition, The Ohio State University, 1787 Neil Avenue, Columbus, OH 43210-1295. Email: smith.23{at}osu.edu

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Objective: This study was designed to determine the timing and magnitude of changes in selenium status in relation to the fluctuation of 17-ß-estradiol during the menstrual cycle and the effect of different phases of the menstrual cycle on dietary selenium intake.

Methods:Plasma 17-ß-estradiol and plasma and erythrocyte selenium and glutathione peroxidase (GPx) activity were measured in fasting blood samples collected in the morning at four times over three phases of the menstrual cycle: early follicular (EF: days 1–3 menstruation), periovulatory (PO; E-1: 1 day before estrogen peak and E: during estrogen peak) and mid-luteal (ML: 7–9 days after ovulation) in healthy women (n = 14) aged 21 to 39 years and with regular menstrual cycles (26 to 30 days). The estrogen peak was confirmed by measurement of the luteinizing hormone surge. Dietary records (three-day) coincided with blood collection for each phase.

Results:Plasma selenium and plasma and erythrocyte GPx activity were greatest during the periovulatory phase, coinciding with the estrogen peak. No differences were observed for erythrocyte selenium or dietary selenium throughout the cycle. A linear relationship existed between estradiol and plasma selenium (p < 0.0027), plasma GPx activity (p < 0.0001), and erythrocyte GPx activity (p < 0.0001).

Conclusions: These results indicate that blood selenium parameters fluctuate during the menstrual cycle such that the phase of the cycle should be considered when assessing selenium status.

Key words: selenium, glutathione peroxidase, estrogen, menstrual cycle, nutritional status

Abbreviations: E = day of 17-ß-estradiol peak • E-1 = day before 17-ß-estradiol peak • EF = early follicular • GPx = glutathione peroxidase • LH = luteinizing hormone • ML = mid-luteal • NADPH = nicotinamide adenine dinucleotide • reduced • PO = periovulatory

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Selenium is an integral component of several selenoproteins including the glutathione peroxidases (GPx), which catalyze the reduction of harmful peroxides [1]. Maintaining an optimum level of selenium and GPx, therefore, is important to protect the host from the development of diseases induced by oxidative damage such as cardiovascular disease [2] and cancer [3]. It is well known that measurements of selenium status in blood are affected by various factors such as dietary selenium intake, age, pregnancy and disease states. An association between sex hormones and selenium status has also been reported, and sex-related differences in selenium status have been observed in animals [4–8] and humans [9,10].

In rats, liver GPx activity has been shown to be greater in females than in males [4,5] and to increase in females after the onset of sexual maturation [6]. These findings support the theory that estrogen increases GPx activity. Testosterone may also have a suppressing effect on liver GPx activity, since castrated male rats experience an increase in liver GPx activity that approaches the level of females [7,8]. A sex hormone effect on selenium utilization has also been indicated in humans since serum selenium concentration in boys decreases during sexual maturation, whereas this change does not occur in girls [9]. Sex differences also appear to influence the distribution of selenium and GPx activity, since erythrocyte GPx activity was shown to be greater in females than in males [10] and renal GPx activity was shown to be greater in males than in female rats [4].

Changes in selenium status during pregnancy also suggest an association between reproductive hormones and selenium metabolism [11–13]. During pregnancy, it is well established that parameters of selenium status decrease [11,12], even independently of dietary selenium intake [13]. Although there has been little information available on the relationship between female sex hormones and selenium status in humans, studies of estrogen treatment in amenorrheic women [14] and of oral contraceptive use [15] have shown an elevation in erythrocyte GPx activity. A specific connection between estrogen and selenium metabolism is also supported by fluctuations in blood selenium parameters during the rat estrous cycle [16]. An interaction between selenium and estrogen receptors is suggested by the fact that selenium will bind to estrogen receptors in cultured breast cancer cells [17] and that the selenium content of breast tumors has been positively correlated to the number of estrogen receptors in the tumor [18]. In addition, postmenopausal women with advanced breast cancer and taking the antiestrogen tamoxifen had normal plasma selenium levels that were significantly greater than those of untreated patients [19].

The effect of the dramatic estrogen fluctuations during the menstrual cycle on the antioxidant systems, including selenium and GPx, has not been studied systematically. The purpose of this study was to determine the timing and magnitude of changes in parameters of selenium status in relation to the fluctuation of 17-ß-estradiol concentration during the menstrual cycle. The effect of different phases of the menstrual cycle on dietary selenium intake was also assessed.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Study Design
Plasma and erythrocyte selenium and GPx activities were determined at four different time points during three phases of the menstrual cycle: once in the early follicular phase (EF: menstruation day 1–3), twice in the periovulatory phase (PO; E-1: one day before the 17-ß-estradiol peak and E: day of 17-ß-estradiol peak) and once in the mid-luteal phase (ML: seven to nine days after ovulation). These time points were chosen because they represent the phases of the cycle in which estrogen levels are the lowest, the highest and at a midpoint, respectively.

Subjects
Subjects were recruited by advertisement on The Ohio State University campus between August and October, 1997, and included students and employees of The Ohio State University Medical Center. The study population consisted of 14 healthy women aged 21 to 39 years with menstrual cycles that were regular and 26 to 30 days in length. Inclusion criteria for the study were the following: 1) maintaining regular menstrual cycles of 26 to 30 days, with the cycle length not changing by more than two days for the three prior months, 2) not taking any type of prescribed medication including oral contraceptives for at least one year prior to study, 3) maintaining a stable body weight with a desirable body mass index (18–25 kg/m²), 4) abstaining from alcohol or drinking less than six drinks/week or less than two drinks/day, 5) non-smoking and non-dieting, 6) no past or ongoing chronic illness, 7) not pregnant or lactating for one year prior to enrollment in the study and 8) not exercising for more than 60 minutes a day or seven hours a week. Procedures for this study were approved by the Institutional Review Board of The Ohio State University, Columbus, Ohio and informed consent was obtained from each subject before enrollment.

Subjects were studied for one menstrual cycle. Preceding the study, participants were informed about the purpose of the study, completed a personal information and medical history sheet to prescreen for menstrual cycle information, existence of ongoing disease and medication histories and were instructed on how to record a three-day dietary intake record.

Sample Collection
Height and weight were recorded, and body mass index (BMI, kg/m²) was calculated. Height was measured without shoes using a stadiometer that is a non-stretchable tape attached to a vertical, flat surface (wall), with a right-angle headboard. A beam scale with nondetachable weights was used to measure weight with clothes but no shoes. Visits were made and blood samples were collected after a six-hour fast during the EF, PO (E-1, and E) and ML phases of the menstrual cycle. The total number and the time of the visits varied depending on the duration of menstruation and the timing of the estrogen peak. For the EF phase, blood samples were obtained between one and three days after menstruation started. In order to detect the day of the estrogen peak, which is followed by the luteinizing hormone (LH) surge, the subjects were asked to use a commercially available urinary LH kit (Quick & Simple, New York, NY) every morning starting on day 9 after the onset of menstruation and continuing until the day after the LH surge. The subjects were instructed to use the test stick with the first urine in the morning and not to urinate at least six hours before the test. Blood drawing for the PO phase began in the morning on menstruation day 11 and continued every morning until the day of or the day after the LH surge. Blood from two days before the LH surge was the sample for E-1. Blood for E was from one day before the LH surge, which coincided with the midpoint of estradiol concentration during the cycle. To confirm the LH surge, the subjects brought the tested strip from the kit to the lab every morning to be examined. The ML phase blood was drawn between six and eight days after the LH surge. Follow up with each subject confirmed that the next cycle began four to six days after the ML phase blood collection.

During each visit, a total of 10 mL of six-hour fasting blood was obtained by venipuncture using heparinized vacutainer tubes appropriate for trace element analysis (Becton Dickinson, Rutherford, NJ). Blood collections for each subject were performed at approximately the same time of day throughout the study period to reduce the variability within each individual. Immediately after the collection, plasma and erythrocytes were separated with refrigerated centrifugation at 4°C (3000 x g for 20 minutes). Samples were stored at -70°C until analysis.

Dietary Intakes
Subjects were instructed to maintain their usual dietary pattern and activity level and to record all food and beverages consumed for the three-day period that immediately preceded the blood collection visits. The completed three-day dietary records were brought to each visit, and any ambiguous dietary information was clarified in person and/or by phone. Dietary records were analyzed for selenium, energy, protein and carbohydrate content using the Food Processor program (enhanced Version 7.11, 1998; ESHA Research, Salem, OR) for each of the three phases of the menstrual cycle. Although Ohio soil is known to be low in selenium content, the selenium intakes and status of people living in Ohio have been shown to be adequate, even in rural areas where farming communities produce much of their own food on soil low in selenium content and availability [20]. The urban population of Columbus, Ohio, sampled for this study, does not rely heavily on locally produced food; therefore, the nutritional analysis software was not altered to reflect any particular selenium content of foods.

Laboratory Analyses
Selenium concentration of plasma and erythrocytes was measured using a spectrofluorometer by the modified method of Kho and Benson [21]. The operating conditions for the spectrofluorometer equipped with a UV lamp were an excitation wavelength of 369 nanometers and an emission wavelength of 525 nanometers. GPx activity of plasma and erythrocytes was determined using hydrogen peroxide by the method of Paglia and Valentine [22]. GPx activity was expressed in micromoles of reduced nicotinamide adenine dinucleotide (NADPH)/gram of protein for plasma and micromoles of NADPH/gram of hemoglobin for erythrocytes. Protein concentration in plasma was assayed by the Lowry method [23]. Hemoglobin concentration of erythrocytes was determined spectrophotometrically using Drabkin reagent [24]. 17-ß-estradiol concentration of plasma was analyzed by a radioimmunoassay using a commercially available estradiol kit (Diagnostic Products Corp., Los Angeles, CA).

Data Analysis
Analysis of Variance (ANOVA) for repeated measurements was performed to detect the possible differences in outcomes for the three different phases of the menstrual cycle. If a significant difference was noted, a paired t test was applied to determine the point of difference. The relationships between plasma 17-ß-estradiol and plasma selenium, plasma GPx activity, erythrocyte selenium and erythrocyte GPx activity were analyzed using a random coefficient regression model taking into account the different intercept and slope of each individual. Since multiple observations were made on the same subjects, a random coefficient model was an effective analysis of covariance for each individual, avoiding the problem of treating the observations independently, which would more likely result in significance by increasing the sample size. Mean ± standard error of the mean (SEM) was used to express all the data. Results analyzed were considered to be significant at p < 0.05. Data were analyzed using the Statistical Analysis Software (SAS) program (Release 6.12, 1988. SAS Institute Inc., Cary, NC).

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Of the thirty-five women who responded to the study advertisement, fifteen women met the eligibility criteria and entered the study. The respondents who were rejected either had irregular menstrual cycles (n = 3), were taking oral contraceptives (n = 12), a selenium supplement (n = 1), or aspirin (known to affect GPx activity [25]) (n = 1), had a BMI greater than 25 kg/m² (n = 1), or were exercising more than six hours a week (n = 2). Among the fifteen subjects who were enrolled, fourteen women completed the study, and one subject who was found to have an anovulatory cycle was excluded. Age, anthropometric data including weight, height and BMI, and the length of the menstrual cycles are shown in Table 1.

View larger version (13K): [in this window] [in a new window]   Fig. 1. Plasma 17-ß-estradiol concentration (Mean ± SEM, n = 14) measured at four time points during three phases of the menstrual cycle (EF: early follicular; E-1: periovulatory, one day before estrogen peak; E: periovulatory, day of estrogen peak; ML: mid-luteal).

View larger version (13K): [in this window] [in a new window]   Fig. 5. Erythrocyte GPx activity (Mean ± SEM, n = 14) measured at four time points during three phases of the menstrual cycle (EF: early follicular; E-1: periovulatory, one day before estrogen peak; E: periovulatory, day of estrogen peak; ML: mid-luteal).

In order to monitor for the potential effect of blood loss and/or hemodilution in the current study, we assessed plasma protein concentration at each stage of the menstrual cycle. Plasma protein concentrations (mg/mL) were significantly different throughout the cycle, being significantly lower during the E phase (55.6 ± 10.1) than during the EF (66.0 ± 9.3, p = 0.006) or ML (65.5 ± 10.3, p = 0.07) phases. Plasma protein at the E-1 phase (58.9 ± 9.2) was also significantly lower (p = 0.07) than that of the EF phase. Erythrocyte hemoglobin concentration (g/dL) was also measured and was significantly greater (p = 0.01) during the EF phase (19.4 ± 1.3) than during the E-1 (18.2 ± 0.7) and E (18.1 ± 0.9) phases, but not different from the ML (18.7 ± 0.9) phase.

Random coefficient regression analysis revealed positive population mean slopes of the line fitting estrogen and plasma selenium (coefficient: 0.0658, p < 0.005), plasma GPx activity (coefficient: 0.0073, p < 0.0001), and erythrocyte GPx activity (coefficient: 0.0241, p < 0.0001). There was no linear relationship observed between dietary selenium intake and plasma selenium, plasma GPx activity, erythrocyte selenium or erythrocyte GPx activity.

Table 2 summarizes dietary intake data computed from the three-day dietary records collected during each phase of the menstrual cycle. Repeated measures ANOVA did not detect any significant differences in intake of total calorie, protein, carbohydrate or selenium intake throughout the menstrual cycle.

	DISCUSSION

The fluctuations observed in selenium measurements throughout the cycle do not appear to be a result of the normal hemodynamics of the menstrual cycle. The significant differences observed for plasma protein concentrations throughout the cycle indicate that hemodilution was occurring around the time of the estrogen peak, with E₂ causing an increase in water retention that was more profound during the periovulatory phase. Kim et al. [28] observed variations in iron-status measures during the menstrual cycle that could be explained by changes in plasma volume and plasma protein concentrations. In contrast, the selenium measurements in this study were greatest during this time of apparent hemodilution and lowest during the phases that hemodilution was not occurring. The plasma GPx activities were corrected for potential changes in plasma protein concentration by being expressed as units of activity per mg protein.

The present study is the first in which blood selenium concentrations, GPx activities and dietary selenium intakes were measured simultaneously to detect phase-related changes during the human menstrual cycle. Plasma selenium and GPx activity have been shown to fluctuate similarly during the rat estrous cycle [16]. Das and Chowdhury [29] also reported changes in plasma selenium concentration during the menstrual cycle, but their plasma samples were collected during the follicular and ovulation phases based on changes in basal body temperature rather than on changes in plasma estrogen concentrations. McAdam et al. [30] presented similar data for differences in plasma selenium and GPx activity during three phases of the menstrual cycle, but neither Das and Chowdhury [29] nor McAdam et al. [30] assessed the impact of selenium intake on the blood selenium measurements throughout the menstrual cycle.

Although variations in plasma selenium concentrations were observed across the menstrual cycle, the values at each phase were always within the reference range for healthy adults (53–161 ng Se/mL) [31]. Since plasma GPx has been shown to contain only 10% to 15% of the plasma selenium [32], increases in the other plasma selenium pools (selenomethionine in methionine containing proteins and selenoprotein P) may be occurring during the menstrual cycle. The lack of change in the erythrocyte selenium content during the menstrual cycle suggests that the concentration of erythrocyte selenium is not affected by menstrual cycle hormonal fluctuations. Therefore, erythrocyte selenium, known to reflect the long-term intake of dietary selenium, may serve as a more constant indicator of selenium status in women of reproductive age. Peiker et al. [33] observed that erythrocyte selenium did not vary throughout pregnancy, whereas serum selenium concentration decreased significantly, further suggesting that erythrocyte selenium is not influenced by reproductive hormone fluctuation. The erythrocyte selenium concentrations for women in this study were greater than that reported by Pleban et al. [34] for healthy women (141 ± 14 ng/mL), but within the range reported by Snook et al. [20] (177–247 ng/mL) for Ohio residents.

Erythrocyte GPx activity measured at each phase was positively associated with plasma 17-ß-estradiol concentrations, reaching the peak values during the PO phase. Massafra et al. [35] also observed cyclic variations in erythrocyte GPx activity during the menstrual cycle and found that the highest activity of erythrocyte GPx coincided with the 17-ß-estradiol peak, supporting the hypothesis that estrogen may be related to the regulation of GPx activity. The results of Larsen et al. [36] also indicate that menstrual hormones influence erythrocyte GPx activity, but their results cannot be accurately related to estrogen fluctuations during the menstrual cycle since blood samples were drawn for GPx analysis only twice per week and were unrelated to plasma estradiol concentrations.

The fluctuation in erythrocyte GPx over the 28 to 30 days of the menstrual cycle is somewhat surprising, considering normal erythrocyte biology. The distribution of selenium within the erythrocyte, however, has been found to be dependent on factors other than just normal protein synthesis. In human erythrocytes, most selenium is not present in GPx, but is associated with the hemoglobin fraction, and the distribution of selenium between GPx and hemoglobin is significantly affected by the form of dietary selenium [37]. Butler et al. [37] found that the percentage of selenium associated with erythrocyte GPx was greater in women taking selenate than in those taking selenomethionine, whereas more selenium was associated with hemoglobin in women taking selenomethionine. In the current study, erythrocyte GPx activity was expressed per gram of hemoglobin, which may partially explain the observed fluctuation in erythrocyte GPx activity. The hemoglobin concentration of the erythrocytes was significantly greater during the EF phase, when the erythrocyte GPx activity was the lowest. This suggests that the distribution of selenium between the hemoglobin and GPx fractions in the (newly made) erythrocytes may be influenced by the phase of the menstrual cycle.

The mechanisms for the observed cyclic changes in selenium parameters during the menstrual cycle are uncertain. Estradiol may be a physiological modulator, regulating selenium concentration and GPx activity directly or indirectly. This assumption is supported by the results of studies on amenorrheic women, in which exogenous estradiol treatment restored plasma estradiol levels and erythrocyte GPx activity to the values of normal cycling women at the mid-follicular phase [14,38]. In contrast, when medroxyprogesterone-acetate treatment was given, there was no increase in erythrocyte GPx activity observed, suggesting that the increase in GPx activity was an estradiol effect [14]. Estradiol treatment has increased erythrocyte GPx activity without changes in malondialdehyde, an indicator of lipid peroxidation [39], suggesting that the increased GPx activity did not result from an increase in lipid peroxide. The effect of estrogen containing oral contraceptives on GPx activity has been more inconsistent and dependent on the level of dose, the duration of use and the type of estrogen administered [15,40,41].

Estradiol’s influence on the cyclic changes in selenium status may involve the redistribution of selenium. Estradiol treatment has resulted in increased renal GPx activity but decreased hepatic GPx activity in male hamsters [42]. Ohwada et al. [43] found that endometrial GPx activity in women is stimulated by estrogen and suppressed by progesterone and that uterine GPx activity in spayed rats can be elevated by exogenous estradiol treatment. Massafra et al. [14] have suggested that estradiol affects the maturation of bone marrow to stimulate the synthesis of active GPx.

It has been suggested that estrogen plays a protective role against cardiovascular disease, partly by decreasing the likelihood of low-density lipoprotein peroxidation [44,45]. Our results suggest that an antioxidant role of estrogen may also be the modulation of GPx activity. This mechanism would have relevance in the postmenopausal population in which a decrease in estrogen level and the associated reduction in selenium status may accelerate oxidative damage after menopause.

Intakes of selenium at each phase of the menstrual cycle exceeded the Recommended Dietary Allowance of 55 µg/day for women [46]. Although variations in food intake have been reported during the menstrual cycle [47,48], there were no differences in dietary selenium, protein, carbohydrate or energy intakes observed throughout the menstrual cycle in this study. Since intake of selenium is the primary determinant for GPx activity and selenium concentration in blood [49], the lack of variation in selenium intake during the menstrual cycle eliminated the possible impact of dietary selenium fluctuations on blood selenium measurements during the cycle.

	CONCLUSION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
In conclusion, blood parameters of selenium status in women of reproductive age fluctuate in synchrony with variations in circulating estrogen concentrations. These results indicate that the phase of the menstrual cycle should be considered when selenium status is assessed in women of reproductive age. Erythrocyte selenium concentration does not fluctuate in response to the menstrual cycle and, therefore, should serve as a more stable marker of female selenium status. This along with the fact that erythrocyte selenium is a well-known marker of long-term selenium intake makes it ideal for epidemiological studies that include measurements of female selenium status. In contrast, measurements of plasma selenium and plasma and erythrocyte GPx activities in females should be interpreted based on timing of the blood sample relative to the phase of the menstrual cycle. In the current study, plasma selenium concentrations increased by approximately 14% during the periovulatory phase. Marginal selenium status, therefore, could be misinterpreted as adequate if blood sampling occurred during this phase.

The results of this study also suggest that reproductive hormone characteristics and fluctuations should be considered when establishing recommendations for selenium intakes in women. These results suggest that a decrease in estrogen concentrations may be accompanied by a reduction in GPx activity, which may accelerate oxidative damage. Since GPx activity has been accepted as the functional biomarker of selenium status in the establishment of the RDA for selenium [46], collection of blood samples for assessment of GPx activity in females should be timed consistently within the menstrual cycle, perhaps avoiding the short-term increase in selenium status markers during the periovulatory phase.

The positive relationship observed between estrogen and selenium status also has implications for the postmenopausal population who have decreased estrogen concentrations along with increased risk of age-related oxidative stress. Further research is warranted to determine the effect of the menopausal drop in estrogen, as well as the effect of estrogen replacement therapy, on parameters of selenium status.

View larger version (13K): [in this window] [in a new window]   Fig. 2. Plasma selenium concentration (Mean ± SEM, n = 14) measured at four time points during three phases of the menstrual cycle (EF: early follicular; E-1: periovulatory, one day before estrogen peak; E: periovulatory, day of estrogen peak; ML: mid-luteal).

View larger version (13K): [in this window] [in a new window]   Fig. 3. Plasma GPx activity (Mean ± SEM, n = 14) measured at four time points during three phases of the menstrual cycle (EF: early follicular; E-1: periovulatory, one day before estrogen peak; E: periovulatory, day of estrogen peak; ML: mid-luteal).

View larger version (11K): [in this window] [in a new window]   Fig. 4. Erythrocyte selenium concentration (Mean ± SEM, n = 14) measured at four time points during three phases of the menstrual cycle (EF: early follicular; E-1: periovulatory, one day before estrogen peak; E: periovulatory, day of estrogen peak; ML: mid-luteal).

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Dr. Ha is currently at the Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, Ohio.

Received July 18, 2002. Accepted September 27, 2002.

	REFERENCES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 

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