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Departments of Obstetrics and Gynecology (L.M.-P., K.R., J.S.T.) and Clinical Chemistry (A.R., P.H., M.P.), University Hospital of Oulu, FIN-90014 Oulu, Finland
Address correspondence and reprint requests to: Professor Juha Tapanainen, Department of Obstetrics and Gynecology, Oulu University Hospital, P.O. Box 5000, FIN-90014 University of Oulu, Finland. E-mail: juha.tapanainen{at}oulu.fi.
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Abstract |
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25 kg/m2] and 32 obese women (BMI 
27 kg/m2) with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months) or ethinyl estradiol (35 µg)-cyproterone acetate (2 mg) oral contraceptive pills. The serum concentrations of CRP were significantly higher in obese than in nonobese subjects at baseline [4.08 ± 0.53 (SE) vs. 1.31 ± 0.28 mg/liter; P < 0.001] and correlated to BMI and to a lesser extent waist-hip ratio, suggesting that the elevated CRP levels may be related to obesity and not only to PCOS itself. During metformin treatment, serum CRP levels decreased significantly from 3.08 ± 0.7 mg/liter to 1.52 ± 0.26 mg/liter at 6 months in the whole study population (P = 0.006) and especially in obese subjects. In contrast, the treatment with ethinyl estradiol-cyproterone acetate increased serum CRP levels from 2.91 ± 0.68 mg/liter to 4.58 ± 0.84 mg/liter (P < 0.001). Whether this effect is related to estrogen action in the liver or whether it reflects increased inflammation process and possible risks for cardiovascular disease remains unclear. The decrease of serum CRP levels during metformin therapy is in accordance with the known beneficial metabolic effects of this drug and suggests that CRP or other inflammation parameters could be used as markers of treatment efficiency in women with PCOS. |
Introduction |
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Insulin-lowering agents such as metformin have been shown to improve insulin sensitivity, hyperandrogenism, menstrual pattern, and ovulatory function in obese and nonobese women with PCOS (10, 11, 12, 13), probably by decreasing central obesity (14, 15, 16, 17). Studies on diabetes patients have indicated that insulin sensitizers decrease serum concentrations of CRP (18), but it is not clear whether the beneficial effects of these drugs on insulin sensitivity in women with PCOS are reflected in changes of serum chronic inflammation parameters. Thus, it was of particular interest to examine the effect of metformin and that of a commonly used oral contraceptive (OC) pill, the ethinyl estradiol-cyproterone acetate (EE-CA) pill, on serum concentrations of CRP in obese and nonobese women with PCOS.
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Subjects and Methods |
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The subjects included in this study had participated in two previous studies on the effects of metformin and the EE-CA pill on insulin sensitivity, glucose tolerance, and hormonal parameters in cases of PCOS (16, 17). Significant obesity is conventionally defined as body mass index (BMI) more than 30 kg/m2. In this study, obesity was defined by the cut-off of BMI = 27 kg/m2, which has been shown to be a critical threshold for insulin sensitivity and metabolic complications of obesity (19) and is generally used in most studies dealing with insulin sensitivity and PCOS (14, 15, 16, 20). Twenty nonobese [mean age 28.2 ± 1.2 (SE) yr, BMI 25 kg/m2 (mean 22.5 ± 0.5 kg/m2, median 22.0, range 7.5 kg/m2)] and 32 obese [mean age 29.5 ± 1.1 yr, BMI 27 kg/m2 (mean 35.2 ± 1.2 kg/m2, median 33.75, range 19.08 kg/m2)] women with PCOS were investigated (Fig. 1
).
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The study was approved by the Ethics Committee of the University of Oulu, Finland, and informed written consent was obtained from each subject.
Protocol
The subjects were randomized to either the metformin group or the EE-CA pill group (ethinyl estradiol 35 µg, cyproterone acetate 2 mg, Diane-Nova, Schering, Helsinki, Finland; 21 d/month followed by a 7-d pill-free period). The metformin dose was doubled after 3 months of treatment (metformin hydrochloride, Diformin, Leiras, Turku, Finland: 500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months) to study the effects of different doses (16, 17).
Waist and hip circumferences were measured to the nearest centimeter with a soft tape at the narrowest part of the torso and at the widest part of the gluteal region. Transvaginal ultrasonography, the oral glucose tolerance test and the euglycemic hyperinsulinemic clamp were performed as described previously (16, 17). The euglycemic hyperinsulinemic clamp technique was used for assessment of insulin sensitivity. Briefly, a priming dose of insulin infusion (Actrapid, 100 IU/ml; Novo Nordisk, Genstofe, Denmark) was administered during the initial 10 min to raise serum insulin acutely to the desired level, at which it was maintained by continuous insulin infusion of 80 mU/m2 body surface area per minute. Blood glucose was clamped at 5 mmol/liter for the next 180 min by adjusting the rate of 20% glucose infusion according to blood glucose measurements performed every 5 min using a photometric assay (HemoCue AB, Ängelholm, Sweden). The insulin sensitivity (M-value) (expressed as milligram per kilogram per minute) was calculated as the mean value for each 20-min interval during the last 60 min of the clamp. The coefficient of variation for blood glucose was less than 4% in all clamp studies. These examinations were performed and venous blood samples were drawn 1–7 d after spontaneous or progestin-induced (dydrogesterone, 10 mg/d for 10 d, four amenorrheic subjects in the obese group and three in the nonobese group) or EE-CA pill-induced menstruation before the treatment and at 3 and 6 months of treatment.
The aim of using progestin in oligomenorrheic subjects was to avoid investigation of subjects (transvaginal sonography and hormone assays) during a spontaneous luteal phase. Although CRP serum level has been shown to increase during the menstrual cycle and correlate with the serum progesterone levels in healthy premenopausal women (23), the increase of CRP levels during hormone replacement therapy in postmenopausal women has been associated with estrogen effect and not with that of progestins (24, 25, 26). To minimize the possible progesterone effect, blood samples were drawn at least a week after the last progesterone pill.
Serum samples had been collected in two recent studies on the effects of metformin and EE-CA pill in nonobese and obese women with PCOS in 1998–2001 (16, 17). All samples were handled similarly and frozen at -20 C for 1–3 yr in both metformin and OC-pill groups. Samples from all subjects who participated in the two previous studies were analyzed (n = 49 before treatment, n = 45 at 3 months of treatment, and n = 35 at 6 months of treatment).
Assays
Concentrations of insulin were determined by RIA (Pharmacia Diagnostics, Uppsala, Sweden), following the instructions of the manufacturers. Serum CRP concentrations were determined by a particle-enhanced immunoturbidimetric method, using a Cobas Integra 700 automatic analyzer (Hoffmann-La Roche, Basel, Switzerland). At a CRP concentration of 6.2 mg/liter the intra- and total assay coefficients of variation were 1.8 and 2.9%, respectively. The detection limit was 0.25 mg/liter.
Statistical analysis
Where there were normally distributed variables, ANOVA for repeated measures was used to compare the clinical, metabolic, and hormonal parameter changes within the metformin and EE-CA groups during the treatment, either without or with logarithmic transformation. The Wilcoxon unpaired test was used for variables with persisting skewed distribution after log transformation.
For comparison between the obese and nonobese groups before treatment and at 3 and 6 months of treatment, a two-tailed t test was used for normally distributed variables, either without or with log transformation. The Mann-Whitney U test was used for variables with persisting skewed distribution after log transformation.
Analysis of correlation between parameters was performed by using Pearson’s bivariate correlation coefficient. Determinants of serum concentrations of CRP before treatment and of the changes in serum CRP levels during both treatments were evaluated by multiple regression analysis. Stepwise method was used to identify the significant predictors (independent variables) of serum CRP levels and their changes during both treatments. Serum CRP level at baseline was entered as a dependent variable, and BMI, waist circumference, waist-hip ratio (WHR), M-value, and serum fasting insulin levels were used as independent variables in the stepwise regression analysis. Similarly, the change in serum CRP levels at 3 and 6 months of treatment was entered as a dependent variable, and changes in BMI, waist circumference, WHR, M-value, and serum fasting insulin levels at 3 and 6 months of treatment were independent variables.
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Results |
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). The changes of these parameters in the obese and nonobese subjects have been published in our previous studies (16, 17).
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). The M-value was significantly lower in obese than nonobese women (14).
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27 kg/m2) and nonobese (BMI 25 kg/m2) subgroups, the decrease of CRP was significant in the obese group (P = 0.02), and a similar tendency was observed in the nonobese group (P = 0.09) (Fig. 2 and Table 2
). In contrast, the treatment with EE-CA increased serum CRP concentrations significantly (Fig. 2 and Table 2).
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). Using the bivariate linear regression model in the whole group of subjects, CRP at baseline was strongly correlated to BMI (P < 0.001), waist circumference (P > 0.001), WHR (P > 0.001), and M-value (P > 0.001) but not to fasting insulin levels.
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Discussion |
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The baseline CRP levels were significantly higher in obese than nonobese subjects with PCOS. This suggests that the increased CRP levels found in women with PCOS (7) may be related to obesity and not just to PCOS. This is supported by the observation that at baseline not only WHR, waist circumference, and M-value but also BMI correlated significantly with serum concentrations of CRP. Furthermore, in the regression analysis BMI, waist circumference and WHR were the only significant determinants of serum CRP levels. Moreover, higher serum CRP levels have previously been observed in obese subjects (27, 28), and weight loss by means of diet (29) or surgical intervention (30) has been shown to decrease the levels. Consistent with the present data, most (7, 31, 32) but not all studies (27) have also demonstrated an independent relationship between central fat accumulation, insulin resistance, and CRP levels in obese subjects. However, whether the total amount of adipose tissue or the pattern of fat distribution, i.e. central obesity, which is strongly linked to insulin resistance, plays a principal role in chronic inflammation, remains to be studied.
Metformin decreased significantly serum CRP levels by 31% (nonobese subjects) and 56% (obese subjects) at 6 months of treatment. Similarly, metformin treatment in diabetic subjects (18) or weight loss by means of diet (29) or surgical intervention (30) have been shown to decrease circulating CRP levels by 33–69%. The mechanisms of this change are of particular interest. Previous studies have suggested that metformin primarily decreases central obesity and secondarily improves insulin action and metabolic disturbances in obese and nonobese women with PCOS (15, 16, 17). Accordingly, in the present study, the improvements of both waist circumference and WHR during metformin treatment were the only significant determinants of serum CRP decrease, whereas BMI, fasting insulin, or M-value play probably a less important role. This is in line with some (27, 33) but not all (34, 35) previous studies showing that waist circumference is a significantly better predictor of the variability of circulating CRP levels than BMI and insulin sensitivity. On the other hand, at 3 months of treatment, the small decrease (1%) in WHR was accompanied by a strong improvement (50%) of CRP, and the changes in WHR and waist circumference could explain only about 20% of the overall decrease of CRP. Moreover, because WHR and waist circumference are strongly correlated with BMI, insulin sensitivity, and insulin levels, complex interactions and mechanisms are probably implied, and larger studies are needed to clarify the mechanisms of metformin action on serum CRP levels in women with PCOS.
Interestingly, serum levels of endothelin-1, a product of endothelial injury, have recently been shown to be elevated in insulin-resistant states such as obesity (36), T2DM (37), and PCOS (38) and decrease significantly during metformin treatment in women with PCOS (38). Furthermore, the results of recent studies have suggested that CRP, rather than being only a marker of low-grade inflammation, may directly promote endothelial dysfunction and complement activation and therefore could play an active role in atherogenesis (39, 40). Thus, the present results strengthen earlier indications that metformin could be an effective drug in the prevention of T2DM and CVD in insulin-resistant women with PCOS.
The EE-CA pill increased significantly serum CRP levels at 6 months of treatment, and, to our knowledge, this is the first study investigating the effect of OC pill treatment on CRP. The results suggest that the OC pill may have metabolic and cardiovascular disadvantages, especially in obese women with insulin resistance. Accordingly, some studies (41) but not all (42) have suggested an increased risk for CVD in users of OCs. On the other hand, because changes in BMI, WHR, fasting insulin, or M-value did not explain the increase of CRP during EE-CA treatment, the mechanism by which EE-CA increases CRP levels and what the consequences are remain speculative. The serum CRP levels have been shown to increase during hormone replacement therapy in postmenopausal women, and this has been associated with estrogen effect and not with that of progestins (24). A direct estrogen action in the liver is also possible because oral estrogens, but not transdermal estradiol, which avoids the first pass liver effect, lead to an increase of serum CRP levels (43, 44). With regard to carbohydrate metabolism, previous studies have indicated an increased risk of T2DM in subjects with low-grade chronic inflammation (45) as well as in past and current users of OCs, compared with nonusers (46, 47). Moreover, most studies in healthy women taking combination OCs have shown increased glucose and/or insulin responses during oral glucose tolerance tests (48, 49) and a significant decrease of insulin sensitivity in obese women with PCOS (50, 51). The results of studies on CA in obese women with PCOS have shown a significant decrease in insulin sensitivity (52) and a worsening of glucose tolerance (16, 53). One way to minimize risks possibly associated with the increase of CRP levels and prevent metabolic disturbances in these women could be to use a combination of an OC pill and metformin, as recently suggested (13). However, further studies are required to clarify the real effect of OC pills on CVD risks in subjects with PCOS.
In conclusion, metformin treatment, in addition to its beneficial effects on hormonal and metabolic parameters in obese and nonobese women with PCOS, was associated with a significant decrease of serum CRP levels, possibly indicating a decrease of the degree of low-grade inflammation. The increase of serum CRP levels observed during EE-CA therapy warrants a careful consideration of benefits and disadvantages of this medication in long-term use, but further studies are needed to clarify whether this effect is related to estrogen action in the liver or whether it actually reflects increased chronic inflammation process. Future studies will show whether CRP or other inflammation parameters should be used as markers of treatment efficiency and improvement of metabolic disturbances in women with PCOS.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; CRP, C-reactive protein; CVD, cardiovascular disease; EE-CA, ethinyl estradiol-cyproterone acetate; M-value, insulin sensitivity; OC, oral contraceptive; PCOS, polycystic ovary syndrome; T2DM, type 2 diabetes mellitus; WHR, waist-hip ratio.
Received October 29, 2002.
Accepted June 27, 2003.
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References |
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activity and serum androgens. J Clin Endocrinol Metab 82:4075–40791 acid glycoprotein, and C-reactive protein. J Lab Clin Med 130:69–75[CrossRef][Medline]
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