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Letters to the Editor |
1 Department of Medicine, University of Hull, Hull, United Kingdom
2 Department of Clinical Biochemistry, Hull Royal Infirmary, Hull, United Kingdom
3 Department of Medicine, York Hospital, York, United Kingdom
aAddress correspondence to this author at: The Michael White Centre for Diabetes and Endocrinology, 220-236 Anlaby Road, Hull Royal Infirmary, Hull HU3 2RW, United Kingdom. Fax 44-1482-675395; e-mail l.cho{at}hull.ac.uk.
To the Editor:
An inverse relationship between increased C-reactive protein (CRP) concentrations and insulin sensitivity has occurred in individuals with polycystic ovarian syndrome (PCOS) (1) and is thought to contribute to an increased risk of coronary heart disease (2). However, no data currently exist on the biological variability of CRP and insulin resistance within the same individuals with PCOS, information that is essential to assess the full relationship between the two measures. We describe a study to establish whether a PCOS patient’s CRP concentration remains within narrow biological limits or varies more widely over a given time period, as well as to correlate its variability to that of insulin resistance.
Twelve overweight [mean (SD) body mass index (BMI), e.g., 33.2 (6.3) kg/m2] Caucasian women, diagnosed with PCOS [median (range) age, 28 (18–31) years], and 11 weight-matched Caucasian women [controls; mean (SD) BMI, 29.9 (3.3) kg/m2], with regular menses (every 28–30 days) and without PCOS [median (range) age, 30 (19–33) years], participated in the study. The BMI in the PCOS group was not significantly greater (P = 0.151) than that of the control group. Diagnosis of PCOS was based on evidence of hyperandrogenemia [defined as free androgen index >8; mean (SD) index: PCOS group, 21.85 (7.95); controls, 4.68 (2.05)], with a history of oligomenorrhea and hirsutism or acne. Mean (SD) concentrations of testosterone and sex hormone–binding globulin (SHBG) in the PCOS group compared with the control group were 4.69 (0.76) vs 2.66 (0.87) nmol/L (P <0.001) and 22.87 (5.06) vs 64.51 (7.65) nmol/L, respectively (P <0.001). Fasting venous blood was collected into serum gel tubes (Becton Dickinson) and 1 fluoride oxalate tube at the same time each day (0800–0900) on 10 consecutive occasions at 4-day intervals. Samples were separated by centrifugation at 2000g for 15 min at 4 °C, and 2 aliquots of the serum were stored at –20 °C within 1 h of collection. Plasma glucose was analyzed in singleton within 4 h of collection. The serum samples were split before assay. All participants gave informed written consent before entering the study, which had been approved by the Hull and East Riding Local Research Ethics Committee.
Serum CRP was measured by the high-sensitivity method on a DPC Immulite analyzer (Euro/DPC), using the manufacturer’s recommended protocol. The interassay CV was 4% using the study samples. Serum insulin was assayed by a competitive chemiluminescent immunoassay, supplied by Euro/DPC. The assay was performed on a DPC Immulite 2000 analyzer (Euro/DPC), according to the manufacturer’s recommended protocol. The CV of this method was 8%, calculated as below, for study samples. The detection limit was 2 milliunits/L, and there was no stated cross-reactivity with proinsulin. Plasma glucose was measured with a Synchron LX 20 analyzer (Beckman-Coulter), according to the manufacturer’s recommended protocol. The CV for this assay was 1%, with a mean glucose value of 5.3 mmol/L during the study period. Fasting glucose in the PCOS group [mean (SD), 4.98 (0.58) mmol/L] was not significantly different from the control group [4.81 (0.32) mol/L]. Fasting insulin was much higher in the PCOS group than in the control group [mean (SD), 23.56 (8.54) vs 7.70 (1.83) µmol/L; P <0.001].
Statistical analysis was performed using SPSS for Windows NT, Ver. 9.0 (SPSS Inc.). We analyzed biovariability data by calculating both intra- and interindividual analytical variances (SDA2, SDI2, SDG2, respectively), according to the methods of Fraser and Harris (3). The insulin resistance was calculated by use of the Homeostasis Model Assessment (HOMA) method [resistance = (insulin x glucose)/22.5] (4).
Before analysis, all serum samples were thawed and thoroughly mixed. The duplicate samples (i.e., 2 per visit) were randomized and then analyzed in a single continuous batch with a single batch of reagents. The distribution of CRP was found to be log-gaussian (by Kolmogorov–Smirnov) in both the women with PCOS and the control group and consequently was logarithmically transformed before statistical analysis.
The CRP concentration in the PCOS group was greater than in the control group [median (range), 3.54 (0.80–61.35) mg/L vs 1.07 (0.18–9.24) mg/L; P = 0.0001, Mann–Whitney test; Fig. 1
)]. For the group with PCOS, the analytical variance contributed 0.2% to the total test variance, intraindividual variance contributed 30.2%, and interindividual variance contributed 69.6%. For the control group, the analytical variance contributed 1% to the total test variance; intraindividual variance, 36.8%; and interindividual variance, 62.2%. After accounting for analytical variation, the mean intraindividual variation was similar in both the group with PCOS and the control group (mean, 1.63 vs 1.76). In contrast, as reported previously for the same individuals (5), the HOMA-IR was not only greater in the group with PCOS [mean (range), 5.85 (1–42.1) units vs 1.67 (0.48–3.49) units; P = 0.001], but was also more variable than in the control group (mean, 1.19 vs 0.23). The interindividual variation in CRP in its natural log for both groups was similar, at 0.5. The critical difference between 2 consecutive CRP samples in an individual patient with PCOS, calculated using the formula 2.77(CVI) (3) on the log-derived data, was –64% or +179% of any initial concentration of CRP. This indicates that a subsequent sample must increase by >179% or decrease by >64% to be considered significantly different from the first.
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This is the first study to examine the biological variation of CRP in women with PCOS, and it shows that although the mean concentration of CRP is higher in individuals with PCOS compared with healthy controls, the intraindividual variation of CRP is similarly large in both groups. Indeed, the potential utility of CRP as a marker of cardiovascular risk may be limited by the magnitude of this variability in both health and disease, as there can be substantial overlap between PCOS and control individuals. Our control group data are in accord with results demonstrated by previous studies suggesting a similarly wide intraindividual variability in CRP of 
30%–40% (6)(7)(8)(9). In contrast, Ockene et al. (10) have suggested that high-sensitivity CRP has a degree of measurement stability similar to that of total cholesterol, therefore providing evidence of potential clinical utility of high-sensitivity CRP screening as a tool for vascular risk prediction. This issue of clinical usefulness, therefore, has yet to be resolved.
The lack of concordance between the variability of CRP concentration and the variability of insulin resistance in PCOS, compared with the controls, indicates that despite the known inverse relationship, the magnitude of CRP changes in the same individual does not closely mirror that of insulin resistance. Therefore, an increased CRP concentration cannot be used as a direct surrogate marker to establish the presence of insulin resistance in this group. There has also been the assumption that, in patients with PCOS, CRP values may reflect the presence of the metabolic syndrome (11)(12); indeed it still might, but insulin resistance alone would not be the sole cause or the main factor. It seems more likely that CRP may reflect or be a marker of many factors that contribute to the syndrome.
References
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