help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Morin-Papunen, L.
Right arrow Articles by Tapanainen, J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morin-Papunen, L.
Right arrow Articles by Tapanainen, J. S.
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4649-4654
Copyright © 2003 by The Endocrine Society

Metformin Reduces Serum C-Reactive Protein Levels in Women with Polycystic Ovary Syndrome

Laure Morin-Papunen, Katriina Rautio, Aimo Ruokonen, Pirjo Hedberg, Matti Puukka and Juha S. Tapanainen

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Low-grade chronic inflammation, reflected in elevated levels of serum C-reactive protein (CRP), has recently been linked to obesity, insulin resistance syndromes such as polycystic ovary syndrome (PCOS), and an increased risk of cardiovascular disease. Because the insulin sensitizer metformin has been shown to improve metabolic disturbances in PCOS, it was of particular interest to examine serum CRP levels during metformin therapy. Twenty nonobese women [body mass index (BMI) <= 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
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is the most common cause of hyperandrogenic anovulatory infertility and is typically associated with peripheral insulin resistance and hyperinsulinemia (1). Hyperinsulinemia enhances androgen action (2) that, in turn, is related to central obesity and worsening of insulin resistance (3). Recently insulin resistance syndromes (4, 5) such as type 2 diabetes mellitus (T2DM) (6) and PCOS (7) have been linked to slightly elevated serum C-reactive protein (CRP) levels in the normal range, which has been shown to predict risk for cardiovascular disease (CVD) (8, 9).

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.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

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. 1Go).



View larger version (35K):
[in this window]
[in a new window]
  		FIG. 1. Flow-chart of the study.

 
Criteria for PCOS were as defined by Homburg (21). All subjects had polycystic ovaries, as shown by vaginal ultrasonography (eight subcapsular follicles or more of 3–8 mm in diameter in one plane in one ovary and increased stroma) and at least one of the following symptoms: oligomenorrhea or amenorrhea, clinical manifestations of hyperandrogenism such as a hirsutism score of more than 7 according to Ferriman and Gallwey (22), acne, and/or an elevated serum testosterone level (>2.7 nmol/liter). Diabetic subjects, smokers, alcohol users, and those taking sex hormones or drugs known to affect lipid metabolism during the 2 months preceding the study were excluded. Twenty nonobese women were treated for 3 months and 17 of them for 6 months (17); and 25 obese women were treated for 3 months and 18 for 6 months (16).

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.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In the metformin group, the mean BMI decreased slightly at 3 months (P = 0.07) and significantly at 6 months. The WHR and fasting serum insulin concentrations decreased significantly at 3 months and 6 months. During the EE-CA treatment, none of these parameters changed (Table 1Go). The changes of these parameters in the obese and nonobese subjects have been published in our previous studies (16, 17).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Main clinical and metabolic parameters of all PCOS subjects before and during treatment

 
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 the difference remained during both treatments (Table 2Go). The M-value was significantly lower in obese than nonobese women (14).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Serum CRP concentrations (mg/liter) of all PCOS subjects and of the obese and nonobese subgroups before and during treatment

 
The serum concentrations of CRP were decreased significantly at 6 months of treatment with metformin (P = 0.006). After dividing the subjects into obese (BMI >= 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. 2Go and Table 2Go). In contrast, the treatment with EE-CA increased serum CRP concentrations significantly (Fig. 2Go and Table 2Go).



View larger version (22K):
[in this window]
[in a new window]
  		FIG. 2. Serum CRP (mg/liter) changes during metformin (n = 16) and EE-CA (n = 19) treatments in the subjects of the study. In the box plots, the median value is given by the line with the first quartile above and below the median enclosed by the box. The 10th and 90th percentiles are indicated by error bars. *, P < 0.05; **, P < 0.01; and ***, P < 0.001, compared with the level before treatment.

 
At baseline and at 6 months of metformin and OC treatments, serum CRP levels were significantly correlated (Pearson’s correlation) with BMI, waist circumference, WHR, and M-value (not with WHR at 6 months of OC treatment) (Table 3Go). 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.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Correlation of serum CRP concentrations with BMI and WHR in PCOS subjects before and at 6 months of metformin and EE-CA treatment

 
In the stepwise analysis, waist circumference (P = 0.001), BMI (P = 0.017), and WHR (P = 0.025) were the only significant determinants of serum CRP levels at baseline, whereas M-value or serum fasting insulin levels were not significant. The changes in WHR (P = 0.03) and waist circumference (P = 0.04) were the only significant determinants of the serum CRP decrease at 6 months of metformin treatment, explaining together about 20% of the overall CRP decrease. No significant determinant was found at 3 months of metformin treatment. During the treatment with the EE-CA pill, no significant determinant of changes of serum CRP levels was found.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study in which the effects of metformin and the EE-CA OC pill on serum CRP levels in women with PCOS have been investigated. The main findings were a significant decrease in serum CRP concentrations during metformin therapy and, conversely, a significant increase during treatment with the EE-CA pill.

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.


   Acknowledgments
 
We thank nurses Mirja Ahvensalmi (Research Unit of the Department of Obstetrics and Gynecology) and Anja Heikkinen (Department of Clinical Chemistry, Oulu University Hospital) for expertise in the technical work and care of the patients, and Risto Bloigu, M.Sc., for advice in the statistical analyses.


   Footnotes
 
This work was supported by grants provided by the University of Oulu, Finnish Gynecological Association, Sigrid Jusélius Foundation, and Academy of Finland.

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.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
  2. Burghen GA, Givens JR, Kitabchi AE 1980 Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113–116[Abstract]
  3. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH 1983 Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 57:304–310[Abstract]
  4. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW 1999 C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19:972–978[Abstract/Free Full Text]
  5. Festa A, D’Agostino Jr R, Howard G, Mykkanen L, Tracy RP, Haffner SM 2000 Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102:42–47[Abstract/Free Full Text]
  6. Temelkova-Kurktschiev T, Henkel E, Koehler C, Karrei K, Hanefeld M 2002 Subclinical inflammation in newly detected type II diabetes and impaired glucose tolerance. Diabetologia 45:151[CrossRef][Medline]
  7. Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N 2001 Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 86:2453–2455[Abstract/Free Full Text]
  8. Ridker PM, Hennekens CH, Buring JE, Rifai N 2000 C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843[Abstract/Free Full Text]
  9. Danesh J, Collins R, Appleby P, Peto R 1998 Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 279:1477–1482[Abstract/Free Full Text]
  10. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ 1994 Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metab Clin Exp 43:647–654
  11. Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK 1998 Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 69:691–696[CrossRef][Medline]
  12. Nestler JE, Jakubowicz DJ 1997 Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 {alpha} activity and serum androgens. J Clin Endocrinol Metab 82:4075–4079[Abstract/Free Full Text]
  13. Elter K, Imir G, Durmusoglu F 2002 Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Hum Reprod 17:1729–1737[Abstract/Free Full Text]
  14. Morin-Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Tapanainen JS 2000 Insulin sensitivity, insulin secretion, and metabolic and hormonal parameters in healthy women and women with polycystic ovarian syndrome. Hum Reprod 15:1266–1274[Abstract/Free Full Text]
  15. Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, Fiorini S, Cognigni GE, Filicori M, Morselli-Labate AM 2000 Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 85:2767–2774[Abstract/Free Full Text]
  16. Morin-Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Martikainen HK, Tapanainen JS 2000 Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 85:3161–3168[Abstract/Free Full Text]
  17. Morin-Papunen L, Vauhkonen I, Koivunen R, Ruokonen A, Martikainen H, Tapanainen JS 2003 Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 88:148–156[Abstract/Free Full Text]
  18. Chu NV, Kong AP, Kim DD, Armstrong D, Baxi S, Deutsch R, Caulfield M, Mudaliar SR, Reitz R, Henry RR, Reaven PD 2002 Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 25:542–549[Abstract/Free Full Text]
  19. Campbell PJ, Gerich JE 1990 Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity. J Clin Endocrinol Metab 70:1114–1118[Abstract]
  20. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A 1987 Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 65:499–507[Abstract]
  21. Homburg R 1996 Polycystic ovary syndrome-from gynaecological curiosity to multisystem endocrinopathy. Hum Reprod 11:29–39[Abstract/Free Full Text]
  22. Ferriman D, Gallwey JD 1961 Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447
  23. Jilma B, Dirnberger E, Loscher I, Rumplmayr A, Hildebrandt J, Eichler HG, Kapiotis S, Wagner OF 1997 Menstrual cycle-associated changes in blood levels of interleukin-6, {alpha}1 acid glycoprotein, and C-reactive protein. J Lab Clin Med 130:69–75[CrossRef][Medline]
  24. Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP 1999 Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 100:717–722[Medline]
  25. Cushman M 2002 Effects of hormone replacement therapy and estrogen receptor modulators on markers of inflammation and coagulation. Am J Cardiol 90:7F–10F
  26. Ridker PM, Hennekens CH, Rifai N, Buring JE, Manson JE 1999 Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 100:713–716[Medline]
  27. Festa A, D’Agostino Jr R, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM 2001 The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 25:1407–1415[CrossRef][Medline]
  28. Ford ES 1999 Body mass index, diabetes, and C-reactive protein among U.S. adults. Diabetes Care 22:1971–1977[Abstract/Free Full Text]
  29. Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET 2002 Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation 105:564–569[Abstract/Free Full Text]
  30. Laimer M, Ebenbichler CF, Kaser S, Sandhofer A, Weiss H, Nehoda H, Aigner F, Patsch JR 2002 Markers of chronic inflammation and obesity: a prospective study on the reversibility of this association in middle-aged women undergoing weight loss by surgical intervention. Int J Obes Relat Metab Disord 26:659–662[CrossRef][Medline]
  31. Pannacciulli N, Cantatore FP, Minenna A, Bellacicco M, Giorgino R, De Pergola G 2001 C-reactive protein is independently associated with total body fat, central fat, and insulin resistance in adult women. Int J Obes Relat Metab Disord 25:1416–1420[CrossRef][Medline]
  32. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB 1999 Elevated C-reactive protein levels in overweight and obese adults. JAMA 282:2131–2135[Abstract/Free Full Text]
  33. Lemieux I, Pascot A, Prud’homme D, Almeras N, Bogaty P, Nadeau A, Bergeron J, Despres JP 2001 Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol 21:961–967[Abstract/Free Full Text]
  34. McLaughlin T, Abbasi F, Lamendola C, Liang L, Reaven G, Schaaf P, Reaven P 2002 Differentiation between obesity and insulin resistance in the association C-reactive protein. Circulation 106:2908–2912[CrossRef][Medline]
  35. Escobar-Morreale HF, Villuendas G, Botella-Carretero JI, Sancho J, San Millan JL 2003 Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women. Diabetologia 46:625–633[Medline]
  36. Ferri C, Bellini C, Desideri G, Di Francesco L, Baldoncini R, Santucci A, De Mattia G 1995 Plasma endothelin-1 levels in obese hypertensive and normotensive men. Diabetes 44:431–436[Abstract]
  37. Takahashi K, Ghatei MA, Lam HC, O’Halloran DJ, Bloom SR 1990 Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 33:306–310[CrossRef][Medline]
  38. Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I 2001 Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. J Clin Endocrinol Metab 86:4666–4673[Abstract/Free Full Text]
  39. Pasceri V, Willerson JT, Yeh ET 2000 Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 102:2165–2168[Abstract/Free Full Text]
  40. Blake GJ, Ridker PM 2002 Inflammatory bio-markers and cardiovascular risk prediction. J Intern Med 252:283–294[CrossRef][Medline]
  41. Vessey MP, Villard-Mackintosh L, McPherson K, Yeates D 1989 Mortality among oral contraceptive users: 20 year follow up of women in a cohort study. BMJ 299:1487–1491
  42. Dunn N, Thorogood M, Faragher B, de Caestecker L, MacDonald TM, McCollum C, Thomas S, Mann R 1999 Oral contraceptives and myocardial infarction: results of the MICA case-control study. BMJ 318:1579–1583[Abstract/Free Full Text]
  43. Lowe GD, Upton MN, Rumley A, McConnachie A, O’Reilly DS, Watt GC 2001 Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein—a cross-sectional population survey. Thromb Haemost 86:550–556[Medline]
  44. Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, Virkamaki A, Hovatta O, Hamsten A, Taskinen MR, Yki-Jarvinen H 2001 Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 85:619–625[Medline]
  45. Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G 1999 Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 353:1649–1652[CrossRef][Medline]
  46. Chasan-Taber L, Willett WC, Stampfer MJ, Hunter DJ, Colditz GA, Spiegelman D, Manson JE 1997 A prospective study of oral contraceptives and NIDDM among U.S. women. Diabetes Care 20:330–335[Abstract]
  47. Rimm EB, Manson JE, Stampfer MJ, Colditz GA, Willett WC, Rosner B, Hennekens CH, Speizer FE 1992 Oral contraceptive use and the risk of type 2 (non-insulin-dependent) diabetes mellitus in a large prospective study of women. Diabetologia 35:967–972[CrossRef][Medline]
  48. Wynn V, Adams PW, Godsland I, Melrose J, Niththyananthan R, Oakley NW, Seed M 1979 Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1:1045–1049[CrossRef][Medline]
  49. Godsland IF, Crook D, Simpson R, Proudler T, Felton C, Lees B, Anyaoku V, Devenport M, Wynn V 1990 The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 323:1375–1381[Abstract]
  50. Korytkowski M, Mokan M, Horwitz M, Berga S 1995 Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. J Clin Endocrinol Metab 80:3327–3334[Abstract]
  51. Nader S, Riad-Gabriel MG, Saad MF 1997 The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women. J Clin Endocrinol Metab 82:3074–3077[Abstract/Free Full Text]
  52. Dahlgren E, Landin K, Krotkiewski M, Holm G, Janson PO 1998 Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod 13:2706–2711[Abstract/Free Full Text]
  53. Prelevic GM, Wurzburger MI, Trpkovic D, Balint-Peric L 1990 Effects of a low-dose estrogen-antiandrogen combination (Diane-35) on lipid and carbohydrate metabolism in patients with polycystic ovary syndrome. Gynecol Endocrinol 4:157–168[Medline]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
D. Heutling, H. Schulz, I. Nickel, J. Kleinstein, P. Kaltwasser, S. Westphal, F. Mittermayer, M. Wolzt, K. Krzyzanowska, H. Randeva, et al.
Asymmetrical Dimethylarginine, Inflammatory and Metabolic Parameters in Women with Polycystic Ovary Syndrome before and after Metformin Treatment
J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 82 - 90.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
S. Tan, S. Hahn, S. Benson, T. Dietz, H. Lahner, L. C Moeller, M. Schmidt, S. Elsenbruch, R. Kimmig, K. Mann, et al.
Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance
Eur. J. Endocrinol., November 1, 2007; 157(5): 669 - 676.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
Y. Takemura, Y. Osuga, O. Yoshino, A. Hasegawa, T. Hirata, Y. Hirota, E. Nose, C. Morimoto, M. Harada, K. Koga, et al.
Metformin Suppresses Interleukin (IL)-1{beta}-Induced IL-8 Production, Aromatase Activation, and Proliferation of Endometriotic Stromal Cells
J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3213 - 3218.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
F. Orio, F. Manguso, S. Di Biase, A. Falbo, F. Giallauria, D. Labella, A. Tolino, G. Lombardi, A. Colao, and S. Palomba
Metformin administration improves leukocyte count in women with polycystic ovary syndrome: a 6-month prospective study
Eur. J. Endocrinol., July 1, 2007; 157(1): 69 - 73.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
E. Diamanti-Kandarakis, T. Paterakis, K. Alexandraki, C. Piperi, A. Aessopos, I. Katsikis, N. Katsilambros, G. Kreatsas, and D. Panidis
Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin
Hum. Reprod., June 1, 2006; 21(6): 1426 - 1431.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
L. Ibanez and F. de Zegher
Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women
Hum. Reprod. Update, May 1, 2006; 12(3): 243 - 252.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
K. Isoda, J. L. Young, A. Zirlik, L. A. MacFarlane, N. Tsuboi, N. Gerdes, U. Schonbeck, and P. Libby
Metformin Inhibits Proinflammatory Responses and Nuclear Factor-{kappa}B in Human Vascular Wall Cells
Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 611 - 617.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
L. Ibanez, C. Valls, and F. de Zegher
Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-{alpha} and the neutrophil/lymphocyte ratio
Hum. Reprod., February 1, 2006; 21(2): 451 - 456.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
F. Orio Jr., S. Palomba, T. Cascella, B. De Simone, F. Manguso, S. Savastano, T. Russo, A. Tolino, F. Zullo, G. Lombardi, et al.
Improvement in Endothelial Structure and Function after Metformin Treatment in Young Normal-Weight Women with Polycystic Ovary Syndrome: Results of a 6-Month Study
J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6072 - 6076.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
F. Gonzalez, J. Minium, N. S. Rote, and J. P. Kirwan
Hyperglycemia Alters Tumor Necrosis Factor-{alpha} Release from Mononuclear Cells in Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5336 - 5342.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
L. Ibanez, A. M. Jaramillo, A. Ferrer, and F. de Zegher
High neutrophil count in girls and women with hyperinsulinaemic hyperandrogenism: normalization with metformin and flutamide overcomes the aggravation by oral contraception
Hum. Reprod., September 1, 2005; 20(9): 2457 - 2462.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. R. Harborne, N. Sattar, J. E. Norman, and R. Fleming
Metformin and Weight Loss in Obese Women with Polycystic Ovary Syndrome: Comparison of Doses
J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4593 - 4598.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
J. Vrbikova and D. Cibula
Combined oral contraceptives in the treatment of polycystic ovary syndrome
Hum. Reprod. Update, May 1, 2005; 11(3): 277 - 291.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Ciampelli, F. Leoni, F. Cucinelli, S. Mancuso, S. Panunzi, A. De Gaetano, and A. Lanzone
Assessment of Insulin Sensitivity from Measurements in the Fasting State and during an Oral Glucose Tolerance Test in Polycystic Ovary Syndrome and Menopausal Patients
J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1398 - 1406.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
K Rautio, J S Tapanainen, A Ruokonen, and L C Morin-Papunen
Effects of metformin and ethinyl estradiol-cyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary syndrome
Eur. J. Endocrinol., February 1, 2005; 152(2): 269 - 275.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. Ibanez and F. d. Zegher
Flutamide-Metformin plus Ethinylestradiol-Drospirenone for Lipolysis and Antiatherogenesis in Young Women with Ovarian Hyperandrogenism: The Key Role of Metformin at the Start and after More than One Year of Therapy
J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 39 - 43.
[Abstract] [Full Text] [PDF]

Home page
 ANGIOLOGYHome page
S. S. Daskalopoulou, D. P. Mikhailidis, and M. Elisaf
Prevention and Treatment of the Metabolic Syndrome
Angiology, November 1, 2004; 55(6): 589 - 612.
[Abstract] [PDF]

Home page
 ANGIOLOGYHome page
S. S. Daskalopoulou, D. P. Mikhailidis, and M. Elisaf
Prevention and Treatment of the Metabolic Syndrome
Angiology, November 1, 2004; 55(6): 589 - 612.
[Abstract] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, C. Valls, S. Cabre, and F. de Zegher
Flutamide-Metformin Plus Ethinylestradiol-Drospirenone for Lipolysis and Antiatherogenesis in Young Women with Ovarian Hyperandrogenism: The Key Role of Early, Low-Dose Flutamide
J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4716 - 4720.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. E. Caballero, A. Delgado, C. A. Aguilar-Salinas, A. N. Herrera, J. L. Castillo, T. Cabrera, F. J. Gomez-Perez, and J. A. Rull
The Differential Effects of Metformin on Markers of Endothelial Activation and Inflammation in Subjects with Impaired Glucose Tolerance: A Placebo-Controlled, Randomized Clinical Trial
J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3943 - 3948.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
N. Boulman, Y. Levy, R. Leiba, S. Shachar, R. Linn, O. Zinder, and Z. Blumenfeld
Increased C-Reactive Protein Levels in the Polycystic Ovary Syndrome: A Marker of Cardiovascular Disease
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2160 - 2165.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
D. J. Salmi, H. C. Zisser, and L. Jovanovic
Screening for and Treatment of Polycystic Ovary Syndrome in Teenagers
Experimental Biology and Medicine, May 1, 2004; 229(5): 369 - 377.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. Ibanez and F. de Zegher
Ethinylestradiol-Drospirenone, Flutamide-Metformin, or Both for Adolescents and Women with Hyperinsulinemic Hyperandrogenism: Opposite Effects on Adipocytokines and Body Adiposity
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1592 - 1597.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
R. Wu, K. H. Van der Hoek, N. K. Ryan, R. J. Norman, and R. L. Robker
Macrophage contributions to ovarian function
Hum. Reprod. Update, March 1, 2004; 10(2): 119 - 133.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available