Menstrual Phase Matters When Measuring CRP Levels to Gauge CVD Risk

SEATTLE – Careful timing in measuring high-sensitivity C-reactive protein during the menstrual cycle can make all the difference in classifying young women’s risk of cardiovascular disease, new data show.

In a study of 259 healthy premenopausal women, high-sensitivity C-reactive protein (hs-CRP) levels fluctuated considerably over the course of the menstrual cycle, with the highest (and most variable) levels seen during menses and the lowest seen at ovulation, researchers reported at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The proportion of women classified as having a high or moderate risk for cardiovascular disease based on their levels of hs-CRP, a marker of chronic inflammation, was significantly greater when levels measured during menses were used (41%) than when levels at ovulation were used (29%).

“The take-home message here is that the measurement of CRP in clinical settings and in future research studies should be standardized to the menstrual cycle phase,” said lead investigator Audrey J. Gaskins, a postbaccalaureate fellow at the National Institute of Child Health and Human Development in Rockville, Md.

“Ideally, [one should] measure CRP around ovulation, when levels are lowest, but that is generally hard to time,” she commented. “So I would say any time other than menses, would be ideal.”

Several lines of evidence suggest that estrogen may modulate inflammation to a clinically relevant extent when it comes to cardiovascular outcomes, according to Ms. Gaskins.

“The risk of coronary events rises in women after menopause, and this corresponds to when endogenous estrogen levels decrease,” she explained. “Also, two recent studies have shown that in regularly menstruating women, there are more acute coronary events in the early follicular phase, when estrogen levels are lowest.”

Ms. Gaskins and her colleagues analyzed data from 259 healthy, normally menstruating women, aged an average of 27 years, and who were followed for up to two menstrual cycles in the BioCycle Study.

Serum samples collected at eight distinct time points during the menstrual cycle were assayed for levels of hormones and hs-CRP. Any hs-CRP values exceeding 10 mg/L were excluded under the assumption that they reflected acute illness.

Ms. Gaskins noted that the population was more diverse than those in previous studies. Some 59% of the women were white, 20% were black, and 21% were of other races. Although 61% had a body mass index in the normal range, 25% were overweight, 10% obese, and 3% underweight (percentages rounded). Seventy four percent were nulliparous, and 4% were smokers.

Study results showed that hs-CRP levels varied widely over the menstrual cycle, she reported. They were highest and also showed the greatest inter-individual variability during menses, and lowest at ovulation, with about a 1.6-fold difference in values between these two time points.

In adjusted models, hs-CRP was significantly associated both with estradiol across the menstrual cycle and with progesterone during the luteal phase. Specifically, hs-CRP levels fell by 24% with each 10-fold increase in estradiol level and increased by 19% with each 10-fold increase in luteal progesterone level.

In a final analysis, the investigators classified the women according to the American Heart Association risk classification system, whereby cardiovascular disease risk is considered high if hs-CRP level is greater than 3 mg/L and moderate if it is 1- 3 mg/L.

Although 32% of women had hs-CRP levels in the high-risk category at at least one time point during the menstrual cycle, only 2% consistently had levels in this category at all eight time points.

Some 41% of the women had hs-CRP levels that placed them in the high- or moderate-risk category during menses, whereas only 29% had high levels at ovulation (P less than .05). The percentages at all other time points, except for the midluteal time point, were also significantly lower than those at menses.

“This is the largest study by far to look at hs-CRP and reproductive hormones in healthy premenopausal women,” noted Ms. Gaskins.

“In regard to estradiol, our results support the hypothesis that estrogen might have anti-inflammatory effects,” she said. “In regard to progesterone, our results support an inflammatory role.”

Having information on other serum markers of inflammation, such as interleukin-6 and tumor necrosis factor-alpha, would have been helpful, she acknowledged. She also noted that owing to strict inclusion criteria, the study population might not apply to all women, even though it was more generalizable than those in previous studies.

Ms. Gaskins reported that she had no relevant conflicts of interest.

SEATTLE – Careful timing in measuring high-sensitivity C-reactive protein during the menstrual cycle can make all the difference in classifying young women’s risk of cardiovascular disease, new data show.

In a study of 259 healthy premenopausal women, high-sensitivity C-reactive protein (hs-CRP) levels fluctuated considerably over the course of the menstrual cycle, with the highest (and most variable) levels seen during menses and the lowest seen at ovulation, researchers reported at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The proportion of women classified as having a high or moderate risk for cardiovascular disease based on their levels of hs-CRP, a marker of chronic inflammation, was significantly greater when levels measured during menses were used (41%) than when levels at ovulation were used (29%).

“The take-home message here is that the measurement of CRP in clinical settings and in future research studies should be standardized to the menstrual cycle phase,” said lead investigator Audrey J. Gaskins, a postbaccalaureate fellow at the National Institute of Child Health and Human Development in Rockville, Md.

“Ideally, [one should] measure CRP around ovulation, when levels are lowest, but that is generally hard to time,” she commented. “So I would say any time other than menses, would be ideal.”

Several lines of evidence suggest that estrogen may modulate inflammation to a clinically relevant extent when it comes to cardiovascular outcomes, according to Ms. Gaskins.

“The risk of coronary events rises in women after menopause, and this corresponds to when endogenous estrogen levels decrease,” she explained. “Also, two recent studies have shown that in regularly menstruating women, there are more acute coronary events in the early follicular phase, when estrogen levels are lowest.”

Ms. Gaskins and her colleagues analyzed data from 259 healthy, normally menstruating women, aged an average of 27 years, and who were followed for up to two menstrual cycles in the BioCycle Study.

Serum samples collected at eight distinct time points during the menstrual cycle were assayed for levels of hormones and hs-CRP. Any hs-CRP values exceeding 10 mg/L were excluded under the assumption that they reflected acute illness.

Ms. Gaskins noted that the population was more diverse than those in previous studies. Some 59% of the women were white, 20% were black, and 21% were of other races. Although 61% had a body mass index in the normal range, 25% were overweight, 10% obese, and 3% underweight (percentages rounded). Seventy four percent were nulliparous, and 4% were smokers.

Study results showed that hs-CRP levels varied widely over the menstrual cycle, she reported. They were highest and also showed the greatest inter-individual variability during menses, and lowest at ovulation, with about a 1.6-fold difference in values between these two time points.

In adjusted models, hs-CRP was significantly associated both with estradiol across the menstrual cycle and with progesterone during the luteal phase. Specifically, hs-CRP levels fell by 24% with each 10-fold increase in estradiol level and increased by 19% with each 10-fold increase in luteal progesterone level.

In a final analysis, the investigators classified the women according to the American Heart Association risk classification system, whereby cardiovascular disease risk is considered high if hs-CRP level is greater than 3 mg/L and moderate if it is 1- 3 mg/L.

Although 32% of women had hs-CRP levels in the high-risk category at at least one time point during the menstrual cycle, only 2% consistently had levels in this category at all eight time points.

Some 41% of the women had hs-CRP levels that placed them in the high- or moderate-risk category during menses, whereas only 29% had high levels at ovulation (P less than .05). The percentages at all other time points, except for the midluteal time point, were also significantly lower than those at menses.

“This is the largest study by far to look at hs-CRP and reproductive hormones in healthy premenopausal women,” noted Ms. Gaskins.

“In regard to estradiol, our results support the hypothesis that estrogen might have anti-inflammatory effects,” she said. “In regard to progesterone, our results support an inflammatory role.”

Having information on other serum markers of inflammation, such as interleukin-6 and tumor necrosis factor-alpha, would have been helpful, she acknowledged. She also noted that owing to strict inclusion criteria, the study population might not apply to all women, even though it was more generalizable than those in previous studies.

Ms. Gaskins reported that she had no relevant conflicts of interest.

SEATTLE – Careful timing in measuring high-sensitivity C-reactive protein during the menstrual cycle can make all the difference in classifying young women’s risk of cardiovascular disease, new data show.

In a study of 259 healthy premenopausal women, high-sensitivity C-reactive protein (hs-CRP) levels fluctuated considerably over the course of the menstrual cycle, with the highest (and most variable) levels seen during menses and the lowest seen at ovulation, researchers reported at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The proportion of women classified as having a high or moderate risk for cardiovascular disease based on their levels of hs-CRP, a marker of chronic inflammation, was significantly greater when levels measured during menses were used (41%) than when levels at ovulation were used (29%).

“The take-home message here is that the measurement of CRP in clinical settings and in future research studies should be standardized to the menstrual cycle phase,” said lead investigator Audrey J. Gaskins, a postbaccalaureate fellow at the National Institute of Child Health and Human Development in Rockville, Md.

“Ideally, [one should] measure CRP around ovulation, when levels are lowest, but that is generally hard to time,” she commented. “So I would say any time other than menses, would be ideal.”

Several lines of evidence suggest that estrogen may modulate inflammation to a clinically relevant extent when it comes to cardiovascular outcomes, according to Ms. Gaskins.

“The risk of coronary events rises in women after menopause, and this corresponds to when endogenous estrogen levels decrease,” she explained. “Also, two recent studies have shown that in regularly menstruating women, there are more acute coronary events in the early follicular phase, when estrogen levels are lowest.”

Ms. Gaskins and her colleagues analyzed data from 259 healthy, normally menstruating women, aged an average of 27 years, and who were followed for up to two menstrual cycles in the BioCycle Study.

Serum samples collected at eight distinct time points during the menstrual cycle were assayed for levels of hormones and hs-CRP. Any hs-CRP values exceeding 10 mg/L were excluded under the assumption that they reflected acute illness.

Ms. Gaskins noted that the population was more diverse than those in previous studies. Some 59% of the women were white, 20% were black, and 21% were of other races. Although 61% had a body mass index in the normal range, 25% were overweight, 10% obese, and 3% underweight (percentages rounded). Seventy four percent were nulliparous, and 4% were smokers.

Study results showed that hs-CRP levels varied widely over the menstrual cycle, she reported. They were highest and also showed the greatest inter-individual variability during menses, and lowest at ovulation, with about a 1.6-fold difference in values between these two time points.

In adjusted models, hs-CRP was significantly associated both with estradiol across the menstrual cycle and with progesterone during the luteal phase. Specifically, hs-CRP levels fell by 24% with each 10-fold increase in estradiol level and increased by 19% with each 10-fold increase in luteal progesterone level.

In a final analysis, the investigators classified the women according to the American Heart Association risk classification system, whereby cardiovascular disease risk is considered high if hs-CRP level is greater than 3 mg/L and moderate if it is 1- 3 mg/L.

Although 32% of women had hs-CRP levels in the high-risk category at at least one time point during the menstrual cycle, only 2% consistently had levels in this category at all eight time points.

Some 41% of the women had hs-CRP levels that placed them in the high- or moderate-risk category during menses, whereas only 29% had high levels at ovulation (P less than .05). The percentages at all other time points, except for the midluteal time point, were also significantly lower than those at menses.

“This is the largest study by far to look at hs-CRP and reproductive hormones in healthy premenopausal women,” noted Ms. Gaskins.

“In regard to estradiol, our results support the hypothesis that estrogen might have anti-inflammatory effects,” she said. “In regard to progesterone, our results support an inflammatory role.”

Having information on other serum markers of inflammation, such as interleukin-6 and tumor necrosis factor-alpha, would have been helpful, she acknowledged. She also noted that owing to strict inclusion criteria, the study population might not apply to all women, even though it was more generalizable than those in previous studies.

Ms. Gaskins reported that she had no relevant conflicts of interest.