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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 776-782
Copyright © 2004 by The Endocrine Society

Plasma Lipid and Lipoprotein Levels during the Follicular and Luteal Phases of the Menstrual Cycle

Junaidah B. Barnett, Margo N. Woods, Stefania Lamon-Fava, Ernst J. Schaefer, Judith R. McNamara, Donna Spiegelman, Ellen Hertzmark, Barry Goldin, Christopher Longcope1 and Sherwood L. Gorbach

Nutrition/Infection Unit, Department of Family Medicine and Community Health, Tufts University School of Medicine (J.B.B., M.N.W., B.G., S.L.G.), and Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University (J.B.B., M.N.W., S.L.-F., E.J.S., B.G., S.L.G.), Boston, Massachusetts 02111; The Lipid Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging (S.L.-F., E.J.S., J.R.M.), Boston, Massachusetts 02111; Departments of Epidemiology (E.H.) and Biostatistics, Harvard School of Public Health (D.S.), Boston, Massachusetts 02115; and Departments of Medicine and Obstetrics and Gynecology, University of Massachusetts Medical School (C.L.), Worcester, Massachusetts 01605

Address all correspondence and requests for reprints to: Dr. Junaidah B. Barnett, Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Room 245, Jaharis Building, 150 Harrison Avenue, Boston, Massachusetts 02111. E-mail: junaidah.barnett{at}tufts.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Estrogen levels are higher during the luteal compared with the follicular phase of the menstrual cycle. It was hypothesized that the luteal compared with the follicular phase has a lipid and lipoprotein profile associated with decreased coronary heart disease (CHD) risk. This was tested using well-defined data from healthy, well-characterized premenopausal Caucasian women under very controlled metabolic conditions. The percent differences in lipid, lipoprotein, and sex hormone levels between the follicular and luteal phases were estimated using generalized estimating equations after adjusting for age, body mass index, calendar time, and season. The low-density lipoprotein cholesterol (LDL-C) level was 6.2% lower (P = 0.015), and the total cholesterol/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios were 5.1% (P = 0.0006) and 8.4% (P = 0.002) lower, respectively, during the luteal phase. Levels of estradiol and other estrogens were significantly higher (by>100% each; P < 0.0001 in all cases) in the luteal phase. These findings support the study hypothesis. Fluctuations in levels of LDL-C and the total cholesterol/HDL-C and LDL-C/HDL-C ratios between menstrual cycle phases need to be considered in the screening and medical monitoring of premenopausal women, especially those with borderline levels. Although small, such fluctuations may prove to be clinically significant in the long run. Studies involving premenopausal women need to more clearly define and validate menstrual cycle phase in the design and interpretation of study results.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INVESTIGATIONS INTO THE ability of estrogens and other sex hormones to alter plasma lipid and lipoprotein levels are important because these factors are significant indicators of cardiovascular risk in both men and women. Numerous studies have consistently shown the influence of exogenous sex hormones on lipid and lipoprotein levels (1, 2, 3, 4), but studies of the effects of menstrual cycle phases on circulating lipid and lipoprotein levels have not shown a consistent pattern (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). Premenopausal women are protected from coronary heart disease (CHD) compared with men and postmenopausal women of the same age (17, 18). Bilateral oophorectomy causes a marked reduction in estrogen production and has been associated with increased CHD risk (18). These findings support the hypothesis that endogenous estrogens affect risk factors of CHD, including plasma lipid and lipoprotein levels. The latter include triglycerides (TG), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or the TC/HDL-C and LDL-C/HDL-C ratios (19, 20, 21, 22, 23). Due to the cycling nature of circulating levels of sex hormones in premenopausal women and their possible impact on levels of lipids and lipoproteins, and hence CHD risk, it is important to determine how these levels vary between the follicular and luteal phases of the menstrual cycle. This is especially important given that even small changes, such as may be seen between menstrual cycle phases, may be clinically relevant over a long period of time (24).

Estrogen levels are higher during the luteal compared with the follicular phase of the menstrual cycle. We hypothesize that compared with the follicular phase, the luteal phase of the menstrual cycle has a lipid and lipoprotein profile associated with decreased risk of CHD. Data to test this hypothesis were obtained from women who participated in a well controlled metabolic study (25, 26). Levels of lipids and lipoproteins as well as sex hormones were determined during the follicular and luteal phases of the menstrual cycle. This study provides important data on the levels of lipids and lipoproteins as well as sex hormones during the follicular and luteal phases of the menstrual cycle under very controlled metabolic conditions.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Forty-eight premenopausal Caucasian women, aged 18–36 yr, were enrolled into the study over a period of 9 yr. The women were healthy, based on a medical history questionnaire and routine blood evaluation. The subjects were not taking medications and were eating a typical American diet (35–40% of calories from fat; 300–400 mg cholesterol/d) as determined by a 4-d food record, which was evaluated by a nutritionist. None of the subjects exercised excessively, followed a vegetarian diet, drank more than 5 oz of alcohol/wk, or smoked, and all had normal eating habits, i.e. did not go on frequent diets or food binges. They all reported to be regularly menstruating for at least 3 months and to have regular menstrual cycles of between 25 and 35 d. They also reported not using oral contraceptives for a minimum of 6 months before enrollment in the study. The study was approved by the institutional review board of Tufts University School of Medicine, and all subjects gave informed consent before starting the study.

The women were started on the metabolically controlled diet 1–2 wk before their next expected menses, and they were studied for one menstrual cycle. Variability between and within subjects with respect to diet was minimized in this study. Each subject was given the same defined Western diet (40% of calories from fat; polyunsaturated:saturated:monounsaturated ratio of 1:2:2; 400 mg cholesterol, 16–17% protein, 43–44% carbohydrate, and 12 g dietary fiber). This combination of dietary fat, fiber, and cholesterol is typical of diets consumed in the United States (27). The dietary fiber provided was a mixture of fiber sources, with approximately equal contributions from grains, legumes, fruits, and vegetables. Caloric intakes were calculated by a nutritionist using standard intakes for sex, age, weight, usual levels of physical activity, and dietary intake to keep body weight constant throughout the study. The Metabolic Research Unit at Jean Mayer Human Nutrition Research Center on Aging at Tufts University prepared all foods consumed by the subjects during the study. Food portions were weighed to 0.1 g, and trays were checked after each meal. Subjects ate three meals a day at the Human Nutrition Research Center on weekdays. In addition to snacks, all weekend and holiday meals were packaged for subjects to take home with them. Subjects were allowed to drink diet ginger ale, black coffee and teas, and herbal teas. Subjects were placed on this diet for about 1–1.5 months depending on when they actually started menstruating after being on the diet. During this time blood samples were collected during the follicular and luteal phases of their menstrual cycle. No significant weight changes occurred during the study.

For the lipid and lipoprotein determinations, a single follicular phase blood sample was collected on any day, 3–9 d after the onset of menses, and a single luteal phase blood sample was collected 10–12 d after a color change was observed using the Ovustick (Monoclonal Antibodies, Inc., Mountain View, CA), a qualitative assay that identifies the LH surge in urine samples 24–36 h before ovulation. Blood samples for follicular hormone levels were collected on 3 consecutive mornings beginning on any d 3–9 after the onset of menses and on 3 alternate days beginning on any day, 6–8 d after a color change was observed using the Ovustick (for identification of ovulation) for the luteal hormone levels. However, in some cases the color change was not observed, and blood samples were collected despite the lack of color change before the women were expected to return to the follicular phase again. In several cases, the women’s menstrual cycle lengths were actually longer than those reported. Thus, the criteria for defining the luteal phase were reevaluated after determination of the actual length of the menstrual cycle of each woman and using the luteal progesterone value obtained. It is known that the number of days in the follicular phase is extended as the number of days of a menstrual cycle is increased, whereas the number of days of the luteal phase remains the same (28, 29). Therefore, counting forward to define days of the luteal phase will result in a wide spread of days defined as luteal depending on the total length of the cycle. Counting backwards to the luteal phase collection from the next menstrual bleeding was used in our analysis because it is independent of cycle length, which varies.

Lipoprotein determinations

Subjects fasted 14 h before blood was drawn for lipid and lipoprotein determinations during the follicular and luteal phases of the menstrual cycle. They were also asked not to perform rigorous physical activity for 24 h and to be seated for 10 min before venipuncture. Blood samples were collected in 0.1% EDTA, spun for 20 min at 2,500 rpm (1,000 g) at 4 C, and analyzed within 48 h. Determination of total plasma cholesterol (TC) and triglycerides (TG) was performed using automated enzymatic methodologies with a Spectrum CCx Chemistry Analyzer (Abbott Diagnostics, Dallas, TX) (30). Plasma HDL-C was determined in supernatants obtained using a dextran sulfate-Mg2+ procedure previously described (31) to precipitate apolipoprotein B-containing lipoproteins. Using a Beckman L8–70 ultracentrifuge (Palo Alto, CA), plasma was subjected to ultracentrifugation at a density of 1.006 g/ml for 18 h at 39,000 rpm (109,000 x g) at 4 C in a 50.3 titanium rotor (Beckman Coulter, Fullerton, CA), and the 1.006 g/ml supernatant and infranatant fractions were separated by tube slicing. Enzymatic methods were used to determine cholesterol concentrations in the 1.006 g/ml infranatant fraction as well as in whole plasma. The TC and HDL-C values obtained have been standardized with the Centers for Disease Control and Prevention-National Heart, Lung, and Blood Institute Standardization Program. Calculations to determine VLDL-C and LDL-C values are consistent with established Lipid Research Clinic methodology (32). The VLDL-C concentrations were calculated as the difference between plasma concentrations and concentrations obtained on the 1.006 g/ml infranatant fraction, and the plasma LDL-C concentrations were calculated as the difference between concentrations obtained from the 1.006 g/ml infranatant fraction and the HDL-C concentrations. TC/HDL-C and LDL-C/HDL-C ratios were also computed. Our coefficient of variations are typically less than 2% for TC and less than 3% for TG and HDL-C.

Hormone determinations

Twenty milliliters of blood were collected each of the 3 mornings to obtain approximately 6–10 ml serum/d by centrifugation at 1400 x g for 22 min at 4 C for hormone analyses. Samples were stored at -70 C for no more than 6 months before sample analysis. Serum estrone, estrone sulfate, estradiol, androstenedione, and testosterone were measured by RIAs involving solvent extraction and Celite chromatography as previously described (33, 34). The percent free testosterone and percent free estradiol were measured using an ultrafiltration technique (35, 36, 37). The diethylaminoethyl cellulose filter technique was used to measure the level of SHBG (36, 37, 38). Progesterone levels during the luteal phase were determined by RIA (39). Prolactin levels were determined using a kit from Serono Laboratories (Norwell, MA), supplied through Ciba-Corning (Medfield, MA). All samples were coded using a random number system, and blinded duplicates were included as a quality control measure.

Statistical methods

Selection of subjects. Only women with menstrual cycle lengths 25–35 d and those with follicular lipid and lipoprotein blood collection within d 4–7 after the onset of menses were included in our analyses. Additionally, only women with luteal lipid and lipoprotein blood collection within 4–8 d before the beginning of the next menstrual cycle who had progesterone levels equal to or greater than 30.2 nmol/liter (or 9.5 ng/ml) during the luteal phase lipid blood collection were included in the analyses. The criterion of equal to or greater than 30.2 nmol/liter (or 9.5 ng/ml) was chosen for luteal phase progesterone levels because this level was selected to rule out anovulatory cycles (40). Thus, in this study, in addition to minimizing factors that could influence lipid and lipoprotein measurements by controlling them in subject eligibility and providing subjects with a metabolically controlled diet, the day of the menstrual cycle that plasma was collected for lipid and lipoprotein data and the criteria used to define the follicular and luteal phases of the menstrual cycle were clearly defined.

As some women went through more than one study protocol (the number of protocols per woman ranged from one to seven), our original dataset comprised 48 women with 90 follicular lipid measurements and 41 women with 66 luteal lipid measurements. Seven women had only follicular lipid measurements. Forty-eight women had 171–190 follicular hormone measurements, and 37–43 women had 157–179 luteal hormone measurements (except only 22 women had 75 measurements of luteal SHBG). Using the criteria defined above, data from 39 women with 58 follicular lipid measurements and 30 women with 42 luteal lipid measurements were included in the final analysis. Of these, data from 25 subjects with both follicular and luteal lipid measures were included in the paired t test analyses. Fourteen women had only follicular measurements, whereas five had only luteal measurements. In the well defined group, 43–44 women had 114–123 follicular hormone measurements, and 33–36 women had 86–93 luteal hormone measurements.

Data analysis. A natural logarithm transformation was used to normalize the distributions of the lipid, lipoprotein, and hormone levels (which were skewed to the left) for valid statistical inference. Data are thus reported as geometric means and SE ranges (emean ± SE).

Generalized estimating equations (41) were used to obtain estimates of the log percent difference (which was converted into the percent difference) in the lipid, lipoprotein, and hormone levels observed between the follicular and luteal phases after adjusting for age and body mass index, calendar time, and season. Because the study took place over a long period of time and across seasons, calendar time was modeled as a continuous variable using the date of the sample as a linear term, and the seasons were modeled as indicators for 3-month periods appropriate to Boston. There were some significant lipid and lipoprotein variations due to seasons in this study. Age was modeled in three-knot restricted cubic splines (42) to allow for a nonlinear relation, whereas body mass index was modeled as a linear effect, because it showed no evidence of nonlinear relations with the lipid and lipoprotein values.

In addition, as mentioned previously, we performed paired t tests comparing the mean change in the levels of lipids and lipoproteins between the luteal and follicular phases on data from women who had values from both follicular and luteal phases (n = 25). The paired t tests are useful in that all subject-specific sources of variation, specifically age, body mass index, season, and calendar time, are completely controlled without any need to model them and possibly misspecify the model as in the multivariate analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go contains the demographic data for a population of 44 study participants who had cycle lengths between 25 and 35 d (mean ± SD, 28.5 ± 2.1). The follicular lipid and lipoprotein samples were collected 5.4 ± 0.5 d (mean ± SD) after the start of menses, whereas the luteal lipid and lipoprotein samples were collected 6.3 ± 0.6 d before the onset of the next bleeding.


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  		TABLE 1. Characteristics of premenopausal Caucasian women

 
Table 2Go presents the levels of lipids and lipoproteins during the follicular and luteal phases of the menstrual cycle, and the percent differences in these levels between the luteal and follicular phases. The levels of TC, TG, and VLDL-C between the follicular and luteal phases of the women’s menstrual cycles were not statistically different. There was a nonsignificant 2.5% increase in the level of HDL-C during the luteal phase. The luteal phase measurement of LDL-C was significantly lower (6.2% lower; P = 0.015) compared with that during the follicular phase. The TC/HDL-C and LDL-C/HDL-C ratios were significantly lower [5.1% lower (P = 0.0006) and 8.4% lower (P = 0.002), respectively] during the luteal compared with the follicular phase measurements. Using paired t tests on 25 women with lipid and lipoprotein measurements for both the follicular and luteal phases, the LDL-C level decreased by 4.6% (P = 0.06), the HDL-C level increased by 2.3% (P = 0.34), the TC/HDL-C ratio decreased by 4.6% (P = 0.04), and the LDL-C/HDL-C ratio decreased by 6.8% (P = 0.1). Changes in the levels of TC, TG, and VLDL-C between phases were not statistically significant.


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  		TABLE 2. Plasma lipid and lipoprotein levels of premenopausal Caucasian women on a typical American diet during the follicular and luteal phases of their menstrual cycle

 
Table 3Go presents serum hormone values for the follicular and luteal phases. As expected, levels of the following hormones were significantly higher during the luteal phase compared with the follicular phase of the menstrual cycle: estrone, estrone sulfate, estradiol, and free estradiol (P < 0.0001 in all cases with percent differences between 104 and 119%). The prolactin level also increased significantly during the luteal phase by 22.2% (P < 0.0001). No significant differences were observed in the levels of testosterone, free testosterone, and SHBG between the two menstrual cycle phases. Progesterone levels were available only in the luteal phase, with a mean of 51.7 nmol/liter (16.3 ng/ml).


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  		TABLE 3. Hormone levels of premenopausal Caucasian women on a typical American diet during the follicular and luteal phases of their menstrual cycle

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study is unique in that it provides important data for a large number of lipid and lipoprotein as well as sex hormone measurements during the follicular and luteal phases of the menstrual cycle obtained from well characterized subjects under very controlled metabolic conditions. The level of LDL-C as well as TC/HDL-C and LDL-C/HDL-C ratios showed significant decreases during the luteal compared with the follicular phase. These findings support our hypothesis of a lipid and lipoprotein profile that is associated with decreased risk of CHD during the luteal compared with the follicular phase of the menstrual cycle. Table 3Go verified the appropriate timing of blood sampling using strict criteria in defining the luteal phase.

Although Mattsson et al. (n = 22) and Nduka and Agbedana (n = 14) found a significant 11% increase in the level of HDL-C during the luteal compared with the follicular phase of the menstrual cycle (9, 13) (Table 4Go), our findings showed a nonsignificant increase of only 2.5% (Table 2Go). The risk of CHD has been shown to decrease by 2–3%/0.026 mM (1 mg/dl) increase in HDL-C (24). Such small changes in levels, although not statistically significant, may be clinically relevant over time. The LDL-C level, however, was significantly lower (by 6.2%) during the luteal phase, and TC was lower by a nonsignificant 2.9% (Table 2Go). Higher magnitudes of change in these levels have been observed previously. Significant decreases of up to 10% have been observed in the levels of TC (8, 10, 12, 13) and LDL-C (9, 16) by other researchers during the luteal compared with the follicular phase (Table 4Go).


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  		TABLE 4. Summary of findings by selected earlier studies1

 
The highly significantly lower TC/HDL-C (5.1%; P = 0.0006) and LDL-C/HDL-C (8.4%; P = 0.002) ratios in the luteal compared with the follicular phase observed in this study tend to indicate the sum of the effects of increased HDL-C as well as decreased TC and LDL-C levels in these two menstrual cycle phases (Table 2Go). These findings support previous significant observations of higher levels of TC/HDL-C (by ~12%) (9), and LDL-C/HDL-C (of up to 18%) (9, 16) in the follicular vs. the luteal phase (Table 4Go). Although TC/HDL-C has been reported to be the best predictor of coronary events in women (21), both TC/HDL-C and LDL-C/HDL-C ratios are considered more sensitive markers for CHD risk than HDL-C levels alone (19).

Exogenous estrogens have been reported to decrease TC and LDL-C and increase HDL-C (43, 44, 45, 46, 47, 48). Estrogen increases the hepatic synthesis of LDL receptor (apolipoprotein B-100), resulting in increased LDL uptake (49). In addition, estrogen treatment has been shown to increase the production of apolipoprotein A-I, a major HDL protein, in both pre- and postmenopausal women (1, 50, 51).

In this study the 2.5% increase in the level of HDL-C in the luteal phase, which may be clinically (24), although not statistically (Table 2Go), significant does indicate the exertion of an estrogenic influence on this lipoprotein level. The degree of the estrogenic influence, however, was not large despite the highly significant increases in estrogen levels (Table 3Go). This may be due to the actions not only of endogenous estrogens, but also of other endogenous hormones, such as progesterone and androstenedione, which are reported to have effects on lipoproteins the opposite that of estrogen (52, 53). Studies examining the effects of exogenous hormones in premenopausal women, however, have found significantly higher magnitudes of change in lipid and lipoprotein levels (1). With administration of exogenous estrogens, hormone levels are relatively high and steady during the study period, possibly overriding the fluctuating levels of endogenous hormones and their influences, thus allowing changes in lipid and lipoproteins to be more easily detected.

Endogenous levels of estradiol, progesterone, and other hormones are periodic throughout the menstrual cycle. In addition to variations in the underlying hormonal patterns between and within a woman, there are considerable variations in menstrual cycle length (54, 55). Menstrual cycle lengths vary from woman to woman and may even vary from month to month for the same woman. It is thus important to control for these variations, because these factors make it difficult to study changes in lipid and lipoprotein levels within the menstrual cycle and are likely to partially account for differences in previous findings (7, 8, 9, 10).

The levels of TC, TG, VLDL-C, LDL-C, HDL-C, TC/HDL-C, and LDL-C/HDL-C have been shown not to change significantly or to either increase or decrease between the follicular and luteal phases of the menstrual cycle (8, 9, 10, 12, 13, 16) (Table 4Go). Differences from previous findings may be due to several factors. Many earlier studies were performed on very few women (n = 8–14) (5, 7, 8, 13, 56). In this study, results from paired t tests using a smaller number of only 25 women showed a significant change only in the TC/HDL-C ratio between phases, not in the other lipid measures, although changes were of similar magnitude to those found in the larger group. With a smaller number of subjects, there was less power to detect the small differences in lipid and lipoprotein measurements observed between the two menstrual cycle phases in the larger sample.

The wide range in the days used in defining the follicular and luteal phases may also be a factor. Only a few studies that related the lipid and lipoprotein levels to menstrual cycle phases included data on hormone levels (9, 12, 13, 56, 57) to verify the menstrual cycle phase. Some studies defined the different phases of the menstrual cycle using only menses date (number of days into the cycle) and daily basal body temperature with or without specifying the day of blood sampling within the menstrual cycle. Progesterone levels during the luteal phase were rarely measured. Often the menstrual cycle phase was specified, but the length of the cycle, with day of blood collection, was not included (10). Including women with menstrual cycle lengths less than 25 d and those more than 35 d may affect findings, because these women may be anovulatory (53) and thus may not follow the usual hormonal fluctuations within a normal menstrual cycle that cause a noticeable effect on differences in the lipid and lipoprotein levels between phases. The fact that the timing of ovulation is difficult to ascertain (53) further compounds the problem, because it also makes it difficult to ensure that luteal lipid and lipoprotein data are actually obtained during the midluteal phase of the menstrual cycle, characterized by peak concentrations of progesterone and estradiol (53).

In addition, the length of the fasting period before blood collection was either not stated or varied from study to study (5, 7, 10). In several studies (5, 7, 9, 11, 56, 57), characteristics of the subject population were not adequately described, omitting information such as the subject’s ethnicity, intake of alcohol, physical activity level, and dietary intake during the study. Also, despite the fact that diet is known to affect lipid and lipoprotein levels, only a few studies were performed under controlled dietary conditions (10, 14, 16). The differences described above make it difficult to determine changes in the lipid and lipoprotein profile between the follicular and luteal phases of the menstrual cycle and to compare reported findings.

Future studies involving women during their reproductive age need to more clearly define and validate menstrual cycle phase in the design and interpretation of study results. It is important to look at multiple samples per subject within each phase and clearly define the timing of and conditions under which samples are being collected. Fluctuations in levels of LDL-C and the TC/HDL-C and LDL-C/HDL-C ratios between menstrual cycle phases, although short term and small, need to be considered in the screening and medical monitoring of premenopausal women, especially those with borderline levels. Although small, such fluctuations may prove to be clinically significant in the long run.


   Footnotes
 
This work was supported by NIH Grant R37-CA-45128, Agriculture Research Service Contract 53-3K06-01, and the General Clinical Research Center funded by the Division of Research Resources of the NIH under Grant MO1-RR-00054.

Abbreviations: CHD, Coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; VLDL-C, very LDL cholesterol.

1 C.L. is deceased. Back

Received March 24, 2003.

Accepted November 10, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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