Oral contraceptives increase C-reactive protein, an infIammatory biomarker

New study results offer potential explanation of complications from birth control pills

When women think about birth control, estrogen, and cardiovascular risk, they often assume that there are no answers. They would appear to be correct.

On the one hand, new pharmacological advancements have provided combination oral contraceptive (OC) formulations with lower-dose estrogen. These formulations have significantly less risk of cardiovascular adverse events compared to the older combined formulations with higher doses. They also provide excellent cycle control, a low incidence of breakthrough bleeding and spotting, and increased patient satisfaction.

On the other hand, the current generation progestins appear less safe than earlier formulations with respect to the risk of blood clotting. Moreover, recent studies have associated current oral contraceptive use with risks for ischemic stroke and myocardial infarction, impaired blood anticoagulant pathways, and increased cardiovascular reactivity. Thus, cardiovascular risk relating to consumption of oral contraceptives still remains.

C-reactive protein (CRP) is a protein in the body whose level increases when blood vessels become inflamed. Measuring cardiovascular risk is thought to be possible by assessing CRP levels. Previously published data has shown that blood levels of CRP are elevated many years before a first heart attack or stroke occurs. Accordingly, a team of researchers set out to investigate the association between current low-dose oral contraceptives and levels of plasma CRP.

A New Study

The authors of “Oral Contraceptive Use and Increased Plasma Concentration of C-reactive Protein” are Darlene M Dreon, DrPH; Joanne L Slavin, PhD; and Stephen D Phinney, MD, PhD, from Galileo Pharmaceuticals, Inc, Santa Clara, CA and the University of Minnesota, St. Paul, MN. They will present their findings at the American Physiological Society’s upcoming conference, Experimental Biology 2003, being held April 11-15, 2003, at the San Diego Convention Center, San Diego, CA.

Background

In a previously published study, investigators used an insensitive, non-quantitative immunoprecipitation technique capable of identifying CRP levels above the current normal range. That study reported the presence of CRP in more than half of women using first generation combined or sequential oral contraceptives of the 1960s. Among women using the then “low dosage” progestin oral contraceptives, the study found no difference in the prevalence of positive serum CRP between this class of OC users versus nonusers.

Given the current availability of the high sensitivity CRP test, it is possible to assess the effects of current low dose oral contraceptives on this biomarker for cardiovascular disease risk. The research team involved in the current study measured the levels of CRP in otherwise healthy, young adult women according to the following methodology.

Methodology

CRP levels were measured using stored samples from 30 healthy, premenopausal women who had previously participated in a randomized, crossover study of the effects of soy intake on sex hormone metabolism in women using OCs and non-users. The study was sited at a university outpatient general clinical research center.

Participants (women aged 18-40 years of age) consumed their habitual diet or a soy-enriched diet for two menstrual cycles each. (Soy consumption had no effect on sex hormone metabolism in OC or non-OC users.) Non-OC users were trained in basal body temperature charting and ovulation testing for verification of follicular and luteal phases. Serum progesterone concentrations were used to confirm ovulation. Four fasting blood samples and 24-hour urine (two mid-follicular and two mid-luteal) were collected from each participant over two menstrual cycles and were stored at –700C until laboratory analysis. OC users provided fasting blood samples on days 8 and 22 after menses. Plasma samples were later thawed and assayed for CRP by use of a high-sensitivity assay.

Results

There were no significant differences in baseline demographic characteristics between oral contraceptive users and nonusers. Plasma CRP levels were two times higher among OC users than among non-users independent of diet assignment, diet treatment order, and phase of the menstrual cycle. In a multivariate model, OC use predicted 32 percent of the variance in CRP levels. As all CRP levels were within a previously established normal range, further study is indicated to establish the clinical significance of the observed elevated CRP levels in OC users.

Conclusions

The results from this research and past studies suggest that estrogenic hormones significantly affect pro-inflammatory pathways. Whether these changes have clinical significance remains to be determined. The present data also showed that CRP levels are higher in the luteal, or post-ovulatory phase, versus the follicular phase. This association was more pronounced in OC users than non-users.

This cross-sectional survey demonstrates that CRP levels are significantly increased among OC users versus non-users. The possibility that these results are due to chance or confounding variables cannot be excluded entirely, and the results need to be confirmed by larger independent studies. The researchers suggest that the impact of OC use on CRP and inflammatory parameters should be investigated in prospective trials.

The American Physiological Society (APS) is one of the world’s most prestigious organizations for physiological scientists. These researchers specialize in understanding the processes and functions underlying human health and disease. Founded in 1887 the Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.