Numerous epidemiological studies have evaluated the role of endogenous estrogens in lipoprotein metabolism. These studies yielded conflicting results, with some observing fluctuating plasma lipid levels throughout the menstrual cycle [17
], while others found a lack of variation in lipid levels over the menstrual cycle [33
]. These differences could be due to study design differences including small sample size, follow-up for only a single menstrual cycle and/or timing of sample collection, heterogeneity in markers of ovulation or inconsistencies in the timing of lipoprotein and hormone measurements. Various methods of timing of lipoprotein cholesterol measurements to menstrual cycle phase were implemented, including determining hormone levels by basal body temperature methods [22
], ovulation charts [18
] or blood samples [18
]. Most studies typically only compared lipoprotein cholesterol levels between the follicular and luteal phases of the cycle, and did not estimate associations between hormone levels and lipoproteins at multiple points during the cycle. Many studies found that only certain component measures of lipoprotein cholesterol (total cholesterol [TC], HDL-C, LDL-C or triglycerides) differ between cycle phases.
Lipoprotein cholesterol levels varied across the menstrual cycle. Specifically, TC and LDL-C were most often lower during the luteal phase, corresponding to the time of the menstrual cycle when estrogen and progesterone levels are high compared with the follicular phase. Furthermore, HDL-C levels were typically highest during the late follicular and periovulatory phases, a finding that tended not to be observed in studies that only compared measurements during the follicular and luteal phases. The increases in TC and LDL-C immediately prior to ovulation, and peak levels of HDL-C at ovulation, are of great physiological importance as cholesterol, and VLDL-C in particular, constitutes the precursor for steroid synthesis and needs to be dramatically increased should a pregnancy occur. summarizes the results of studies that compared levels between phases. The mean changes in TC levels across the menstrual cycle varied between 4 and 10%, LDL-C between 4 and 12.5% and HDL-C by 11% across the studies evaluated. The mean intraindividual variability reported for TC ranged from 8 to 19%. Triglyceride levels did not vary cyclically throughout the cycle. Certain studies also reported various lipoprotein particle subfractions, although further work is needed in this area.
Summary of findings by selected studies evaluating cyclic changes in lipoprotein cholesterol levels across the menstrual cycle†.
Not only do lipoprotein cholesterol levels differ between the follicular and luteal phases, but they have been shown to vary on a day-to-day basis throughout the cycle. In the largest study to date, hormones and lipoprotein cholesterol were measured at up to eight visits per cycle, for up to two cycles in a cohort of 259 healthy, regularly menstruating women [42
]. Collection of these fasting blood samples was timed to specific phases of the menstrual cycle using fertility monitors. These multiple measurements enabled evaluation of the patterns of means and the variability of lipoprotein cholesterol levels across the cycle. As shown in , TC and LDL-C follow a similar pattern across the menstrual cycle, with levels increasing rapidly after menses, peaking during the follicular phase and then declining throughout the luteal phase. The peak levels of TC and LDL-C were observed during the follicular phase prior to the rise and peak of estrogen, with TC and LDL-C levels declining during the luteal phase, corresponding to rising and peak concentrations of estrogen and progesterone. HDL-C levels were highest around ovulation, corresponding to high levels of estrogen, whereas triglyceride levels varied without a consistent pattern across the cycle. Interestingly, variability in lipoprotein cholesterol measurements fluctuated across the cycle (). Minimum variation in TC, LDL-C and triglycerides was observed during menses and around ovulation, with HDL showing the most variability around ovulation. Many of the other studies reviewed observed similar variation in lipoprotein levels (standard errors or variance) during the follicular and luteal phases of the cycle, while some did not report the levels of variability. Among the studies reporting measurements during menses [18
], most detected a decrease in the variability of TC levels [18
], while an increase in variability in HDL levels around ovulation was observed in one other study [29
Mean levels of total cholesterol, LDL-C, HDL-C, triglycerides and estrogen levels across the menstrual cycle among 259 women enrolled in the BioCycle Study.
Variance in lipoprotein cholesterol measurements during different phases of the menstrual cycle among 259 women enrolled in the BioCycle Study.
Owing to the observed day-to-day changes in both the mean and variability of lipoprotein cholesterol levels, studies have analyzed the association between estrogen and lipoprotein cholesterol levels across the cycle (). Positive correlations and associations between HDL and estrogen levels were observed. TC and LDL-C levels were inversely associated with estrogen levels, although findings were not statistically significant in all of the studies. In the most recent study, endogenous estrogen was also positively associated with TC and HDL-C and inversely associated with LDL-C in acute effects models (which consider hormones and lipoprotein cholesterol measured on the same day), and significantly and inversely associated with TC and LDL-C levels during the cycle in persistent effects models (which consider hormones measured at the visit immediately prior to measurement of lipoprotein cholesterol levels) [42
]. These models took into account repeated measurements across the cycle, levels of other circulating reproductive hormones and other factors known to impact these associations, such as age and BMI [42
]. Further adjustment for physical activity and dietary intake did not alter the results. These findings suggest that estrogen has a rapid effect on increasing TC and HDL-C levels and decreasing LDL-C levels, as well as nonacute effects on decreasing LDL-C, which lead to decreases in TC.
Selected studies evaluating the association between lipoprotein cholesterol levels and estrogen.
Taken together, these studies show cyclic changes in lipoprotein cholesterol levels during the menstrual cycle, which are associated with circulating estrogen levels. The changes in lipids between different days of the menstrual cycle are fairly small, but should be taken into account when evaluating lipoprotein cholesterol levels among reproductive-aged women, particularly in light of the corresponding differences in lipid variability observed over the course of the menstrual cycle.