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Original Article |
Departments of Obstetrics and Gynecology (L.M.-P., R.K., H.M., J.S.T.) and Clinical Chemistry (A.R.), University Hospital of Oulu, FIN-90014 Oulu, Finland; and Department of Medicine (I.V.), University Hospital of Kuopio, FIN-70211 Kuopio, Finland
Address all correspondence and requests for reprints to: Dr. Juha Tapanainen, Department of Obstetrics and Gynecology, University Hospital of Oulu, P.O. Box 5000, FIN-90014 University of Oulu, Oulu, Finland. E-mail: juha.tapanainen{at}oulu.fi.
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Abstract |
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Introduction |
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The data as regards insulin resistance in nonobese PCOS women are controversial, but the results of several studies have suggested intrinsic insulin resistance in these women (15, 16, 17, 18, 19, 20, 21). Twenty to 50% of women with PCOS are of normal weight or lean. Recently, insulin-sensitizing drugs like metformin have been shown to improve ovulation and decrease serum testosterone (T) levels in nonobese PCOS women, (22) even with normal indices of insulin sensitivity (23), and in young hyperandrogenic hyperinsulinemic women (24, 25, 26).
Oral contraceptive (OC) pills are used commonly in the treatment of menstrual disturbances and hyperandrogenism in women with PCOS. They increase serum SHBG concentrations, thus decreasing the levels of bioavailable androgens. However, OCs have been shown to slightly worsen glucose tolerance in healthy women of normal weight (27, 28) as well as in obese PCOS subjects (29).
The aim of the present study was 2-fold: firstly, to study further the mechanisms of action of metformin in nonobese women with PCOS; and secondly, to compare the effects of metformin with those of the ethinyl estradiol (EE)-cyproterone acetate (CA) pill. The endpoints of the study were the effects of these two treatments on insulin sensitivity and secretion, glucose and fat metabolism, and endocrine and biochemical parameters.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty nonobese [body mass index (BMI) < 25 kg/m2] women with PCOS were recruited from the Reproductive Endocrine Unit at Oulu University Hospital, Finland (Table 1
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8 subcapsular follicles of 3- to 8-mm diameter in one plane in one ovary and increased stroma) and at least one of the following symptoms: oligomenorrhea or amenorrhea (9 of 10 in the metformin group and 8 of 10 in the EE-CA group), clinical manifestations of hyperandrogenism such as a hirsutism score of more than 7, according to Ferriman and Gallwey (Ref.31 ; 5 of 10 in the metformin group and 2 of 10 in the EE-CA group), acne (1 of 10 in both groups), and/or an elevated serum T level (>2.7 nmol/liter; 4 of 10 in the metformin group and 3 of 10 in the EE-CA group; Table 1
). 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. Three women stopped the treatment after the 3-month control visit; one (metformin) moved away, one (metformin) stopped for personal reasons, and one (EE-CA) stopped because of headache and high blood pressure. Thus, 20 women were treated for 3 months, and 17 were treated for 6 months.
The study was approved by the Ethics Committee of the University of Oulu, Finland, and informed written consent was obtained from each subject.
Protocol of the study
The subjects were randomized to either the metformin group or the EE-CA pill group [EE, 35 µg; CA, 2 mg, Diane-Nova (Schering, Helsinki, Finland); 21 d/month, followed by a 7-d pill-free period]. In nonobese PCOS women, metformin doses ranging from 1275–1500 mg have been shown to be effective (7, 25, 26). However, to investigate whether a higher dose was more effective, as shown in obese subjects (29), the metformin dose was doubled after 3 months of treatment [metformin hydrochloride (Diformin, Bristol-Myers Squibb Co., Leiras, Finland), 500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months].
All subjects were evaluated 1–7 d after spontaneous, or progestin-induced (dydrogesterone, 10 mg/d for 10 d; amenorrheic subjects, four subjects in both groups), or EE-CA pill-induced menstruation before treatment and at 3 and 6 months of treatment. The aim of using progestin in these subjects was to avoid examinations (ultrasonography and hormone assays) during a spontaneous luteal phase. We used dydrogesterone because it has only a negligible effect on insulin sensitivity (32). Furthermore, to assure a minimal effect, the examinations were performed at least 7 d after the last progestin pill.
Clinical parameters and ultrasonography
Blood pressure was measured after a 20-min rest in a sitting position. Diastolic blood pressure was measured as Korotkoff phase V. 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 (General Electric RTX 200, General Electric, Milwaukee, WI; with a 6.5-MHz probe) was performed to measure ovarian volumes and the number of follicles. Volume determinations were performed using the formula for the volume of an ellipsoid: 0.523 x length x width x thickness (33).
Oral glucose tolerance test (OGTT)
After an overnight fast of 10–12 h, all subjects underwent an OGTT (a load of 75 g glucose in 300 ml water). Venous blood samples for blood glucose, serum insulin, and serum C-peptide assays were drawn at 0, 15, 30, 60, and 120 min. A glycemic response to the OGTT was defined according to the 1997 American Diabetes Association criteria: diabetes mellitus at 0 min, at least 6.1 mmol/liter; and/or at 120 min, at least 10 mmol/liter; impaired glucose tolerance (IGT) at 0 min, less than 6.1 mmol/liter; and at 120 min, 6.7–10.0 mmol/liter; impaired fasting glycemia at 0 min, at least 5.6 and less than 6.1 mmol/liter; and at 120 min, less than 6.7 mmol/liter; normal glucose tolerance at 0 min, less than 5.6 mmol/liter; and at 120 min, less than 6.7 mmol/liter (34). Early phase insulin secretion (insulinogenic index) was calculated as the ratio of the increment of serum insulin 30 min after the oral glucose load to blood glucose concentration 30 min after the glucose load [(30-min insulin minus fasting insulin)/30-min glucose] (35). The insulinogenic index has previously been shown to correlate strongly with the first phase insulin response after an iv glucose tolerance test (r = 0.88; Ref.36). Early phase C-peptide secretion was calculated as (30-min C-peptide minus fasting C-peptide)/30-min glucose. Early phase C-peptide secretion reflects ß-cell secretory capacity more accurately than insulin (37) because its hepatic extraction, unlike that of insulin, is negligible (38). The incremental insulin (AUCins) and glucose (AUGgluc) areas under the curve were calculated by the trapezoidal method. The fasting serum C-peptide x 1000/fasting serum insulin molar ratio was calculated as an index of hepatic insulin extraction in the fasting state (39).
Euglycemic hyperinsulinemic clamp
The euglycemic hyperinsulinemic clamp technique was used for assessment of insulin sensitivity (40). A priming dose of insulin infusion (Actrapid, 100 IU/ml; Novo Nordisk A/S, Genstofe, Denmark) was administered during the initial 10 min to raise serum insulin acutely to the desired level, where 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 M-value (expressed as µmol/kg·min) 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. Because it has been previously shown that in nondiabetic hyperandrogenic subjects, endogenous glucose production is negligible at this insulin infusion rate, the amount of glucose infused may be considered to be equivalent to whole body glucose uptake, i.e. whole body glucose disposal (41). Blood samples for the assay of serum lactate, insulin, and FFAs were drawn at 0, 120, 140, 160, and 180 min.
Calorimetry
Indirect calorimetry was performed with a computerized flow-through canopy gas analyzer system (Deltatrac, TM Datex, Helsinki, Finland) in connection with the euglycemic clamp, as previously described (42). This device has a precision of 2.5% for O2 consumption and 1.0% for CO2 production. On the day of the experiment, gas exchange (O2 consumption and CO2 production) was measured for 30 min after a 12-h fast before the clamp and during the last 30 min of the clamp. The values obtained during the first 10 min of both time periods were discarded, and the mean value for the remaining 20 min of data were used for calculation. Protein, glucose, and lipid oxidation were calculated according to Ferrannini (43). Protein oxidation was calculated on the basis of the urinary nonprotein nitrogen excretion rate (43). The fraction of carbohydrate nonoxidation during the euglycemic clamp was estimated by subtracting the carbohydrate oxidation rate (determined by indirect calorimetry) from the glucose infusion rate (determined by the euglycemic clamp).
Assays
The concentrations of SHBG, LH, and FSH were analyzed by fluoroimmunoassays (Wallac, Inc. Ltd., Turku, Finland), and RIAs were used for dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), C-peptide (Diagnostic Products Corporation, Los Angeles, CA), cortisol (Orion Diagnostica, Oulunsalo, Finland), leptin (Linco Research, Inc., St. Charles, MO), and insulin (Pharmacia Diagnostics, Uppsala, Sweden), following the instructions of the manufacturers. Concentrations of human serum IGF binding protein (IGFBP)-1 were determined by immunoenzymometric assay using commercial reagents (Medix Biochemica, Kauniainen, Finland), and concentrations of T were determined by using an automated chemiluminescence system (Ciba-Corning ACS-180, Ciba-Corning Diagnostics Corp., Medfield, MA). The free androgen index (FAI) was calculated according to the equation: (T x 100)/SHBG. Serum levels of FFAs, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood glucose were determined by standard methods. The serum low-density lipoprotein (S-LDL) level was calculated with the Friedewald formula if the serum triglyceride level was below 4 mmol/liter; if the triglyceride level was at least 4 mmol/liter, it was precipitated by heparin in isoelectric point.
The intra- and interassay coefficients of variation were 1.3 and 5.1% for SHBG, respectively; 4.9 and 6.5% for LH; 3.8 and 4.3% for FSH; 6.5 and 7.9% for DHEA; 5.3 and 7.0% for DHEAS; 5.0 and 8.6% for A; 5.0 and 5.4% for 17-hydroxyprogesterone; 4.0 and 5.6% for T; 4.0 and 4.3% for cortisol; 5.3 and 7.2% for C-peptide; 5.3 and 7.6% for insulin; 3.4 and 7.4% for IGFBP-1; 5.0 and 6.0% for leptin; 0.7 and 2.3% for cholesterol; 0.9 and 2.1% for triglycerides; 0.5 and 3.6% for HDL-cholesterol; and 2.0 and 2.9% for LDL-cholesterol.
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 metformin and EE-CA groups before treatment and at 3 and 6 months of treatment, Student’s 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.
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Results |
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In the metformin group, the mean BMI of the subjects was decreased significantly at 3 months (P = 0.04) and slightly at 6 months (P = 0.08), and the waist to hip ratio (WHR) decreased significantly. In the EE-CA group, the BMI increased significantly at 3 months (P = 0.049) and slightly at 6 months (P = 0.1), but the WHR did not change (Table 1 and Fig. 1).
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). Menstrual cyclicity was improved in four of the eight subjects at 6 months of metformin treatment. None of the women became pregnant during the treatment. The mean ovarian volumes did not change significantly during metformin treatment (6.1 ± 0.9 cm3 before treatment and 6.0 ± 0.5 cm3 at 6 months; P = 0.3) but decreased significantly in the EE-CA group at 6 months (7.8 ± 1.7 vs. 4.2 ± 0.5 cm3; P = 0.03). At 6 months of treatment, the mean number of follicles had decreased slightly in the metformin group (from 10.5 ± 0.4 to 8.8 ± 0.9; P = 0.09) and significantly in the EE-CA group (from 9.7 ± 0.5 to 6.6 ± 0.6; P = 0.006).
Metabolic parameters
Metabolic parameters are presented in Tables 1 and 2 and Figs. 2 and 3.
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Fasting glucose levels and blood glucose levels during the OGTT had decreased at 3 months of metformin treatment, but the differences had disappeared at 6 months (Fig. 2). Consequently, AUCgluc tended to be decreased in the metformin group at 3 months [from 12.6 ± 0.7 (SEM) to 11.0 ± 1.1 mmol/liter·h; P = 0.07] but it had returned to the starting level at 6 months. EE-CA treatment did not significantly affect AUCgluc (Fig. 2).
In the metformin group, fasting insulin concentrations had decreased significantly at 3 months and 6 months (Table 1 and Fig. 2). AUCins decreased slightly in the metformin group, from 520.6 ± 92.4 to 371.8 ± 70.3 pmol/liter·h at 6 months (P = 0.09; Fig. 2), but it did not change in the EE-CA group (Fig. 2).
Early phase insulin secretion (insulinogenic index) was decreased significantly at 6 months in the metformin group (P = 0.04). However, serum C-peptide concentrations were increased significantly at 6 months of metformin in the fasting state and at 30 min in the OGTT (P = 0.01). Consequently, early phase C-peptide secretion tended to be increased at 6 months of metformin (P = 0.07; Table 1). Hepatic insulin extraction in the fasting state was significantly increased in the metformin group, but it did not change in the EE-CA group (Table 1 and Fig. 3).
M-values, fasting and clamp (insulin-mediated) glucose oxidation and nonoxidation rates did not change during either treatment (Table 2).
Energy expenditure, lipid oxidation, and serum FFA levels
Fasting energy expenditure had decreased (P = 0.04) during metformin therapy at 3 months, and during the clamp it was increased significantly in the EE-CA group at 6 months (P = 0.01). The insulin-stimulated respiratory quotients (RQs) were increased (P = 0.002) at 3 months of metformin treatment (Table 2).
Insulin-stimulated serum concentrations of FFAs were decreased significantly at 3 months and slightly at 6 months in the metformin group, and they were increased significantly (P = 0.02) in the EE-CA group at 6 months. Insulin-stimulated lipid oxidation decreased from 0.44 ± 0.03 mg/kg·min before treatment to 0.29 ± 0.03 mg/kg·min at 3 months (P = 0.01), and it was 0.32 ± 0.04 mg/kg·min at 6 months (P = 0.09) during metformin therapy (Table 2).
Endocrine parameters and lipids
The endocrine parameters are presented in Table 3. Serum T, A, and DHEA concentrations and the FAI decreased significantly in both groups. In the EE-CA group, serum leptin levels and serum fasting cortisol concentrations increased significantly (Table 3).
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Discussion |
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The main findings of the present study, i.e. improvement of hyperinsulinemia and hyperandrogenism by using metformin, are in keeping with the results of previous studies on obese insulin-resistant women with PCOS (5, 6, 8, 9, 29), as well as those on nonobese subjects (7, 22). In obese women, the primary mechanisms of metformin action have been suggested to be improvement of insulin sensitivity (8, 9, 44) and primary reduction of central obesity inducing secondarily an improvement of insulin action (14, 29). On the other hand, whether or not metformin improves insulin sensitivity independently of weight loss is still controversial (45, 46), and one way to answer this question is analysis of the effects of metformin in nonobese PCOS women. Moreover, because the role of insulin resistance and hyperinsulinemia in nonobese women with PCOS is still controversial, it is of particular interest to investigate the effects of metformin in this group of subjects. A number of mechanisms, such as enhancement of insulin first phase secretion (20, 47), increased abdominal obesity (13, 19, 20, 47, 48, 49, 50), or a defect in hepatic extraction of insulin (51), have been proposed as primary pathogenic factors of PCOS in nonobese women. Thus, there are several potential end points at which metformin could exert its action. Moreover, a recent study has suggested that metformin may be effective in PCOS even in the absence of marked insulin resistance (23).
In the present study, hepatic insulin extraction, i.e. insulin clearance, increased significantly during metformin treatment, explaining the reduction of serum insulin levels at baseline and at 30 min in the OGTT, and consequently that of early phase insulin secretion (insulinogenic index). However, because no simultaneous decrease of C-peptide secretion was observed, this finding did not reflect any real decrease in insulin secretion by the ß-cells, in line with previous data indicating the lack of a direct effect of metformin on insulin secretion (52). In fact, fasting serum C-peptide concentrations and early phase C-peptide secretion increased, probably to compensate for the increase in insulin clearance. The observed improvement in hepatic excretion of insulin could be one of the main mechanisms of metformin action in nonobese PCOS subjects, secondarily reducing serum insulin concentrations and improving hyperandrogenism. A similar improvement in hepatic extraction of insulin has also been observed in obese PCOS women during metformin treatment, but the change was not significant, suggesting that the effect of this therapy and/or the pathogenesis of PCOS differs in nonobese and obese women (53, 54). A primary defect in hepatic insulin sensitivity, and consequently in hepatic insulin extraction, resulting in hyperinsulinemia and secondarily in insulin resistance and hyperandrogenism, could induce the development of this syndrome in nonobese women, as suggested previously (51).
The concomitant improvement in insulin clearance and the decrease of serum insulin levels without any change in glucose tolerance during metformin treatment suggest an improvement in insulin action. This finding is in line with our previous results in obese women, in which we observed subtle improvements in hepatic insulin excretion and insulin sensitivity, leading to a significant decrease of hyperinsulinemia in these subjects (29). Furthermore, the results of previous studies have suggested that metformin could primarily reduce central obesity and decrease the release of free FFAs (i.e. lipolysis) from adipose tissue (14, 29). According to a hypothesis proposed by Randle et al. (55), the decreased competition between serum glucose and FFAs as energy substrates in peripheral tissues could result in an improvement of glucose oxidation and consequently insulin sensitivity and hyperinsulinemia (14, 29, 55). In support of this concept, a significant decrease of WHR was also observed in nonobese subjects in this study. Moreover, despite the absence of significant change in insulin sensitivity (M-value) or in the rates of glucose oxidation and nonoxidation, a moderate decrease of serum FFA concentrations and the rate of lipid oxidation in the clamp occurred during metformin therapy.
The lack of a significant improvement of the M-value is surprising, but it can be explained by the fact that the antilipolytic effect of insulin, i.e. suppression of FFA release from adipose tissue, and consequently the improvement of glucose use induced by metformin could have been better observed at lower insulin concentrations than those observed during the hyperinsulinemic clamp (56, 57).
In accordance with the results of most studies on metformin in obese PCOS women (5, 8, 9, 29), but not with all (58), serum androgen levels and the FAI decreased significantly. Because these changes were moderate and most women were only slightly hirsute, the treatment with metformin had no significant effect on hirsutism. Hyperinsulinemia has been shown to induce hyperandrogenism (1, 59), but androgens may produce mild insulin resistance by increasing the number of less insulin-sensitive type IIb skeletal muscle fibers (60) and by inhibiting muscle glycogen synthase activity (61). However, decreasing androgen levels by way of GnRH agonist treatment (62) or antiandrogens (41) does not completely restore normal insulin sensitivity in the short term, and it has been suggested that longer treatment may be needed for metabolic changes to be evidenced (41). In this study, metformin was actually used at higher doses than in obese women, when related to the BMI of the subjects, and this could induce a different mechanism of action, for example in the ovary. Moreover, metformin has been suggested to directly inhibit androgen production in human theca cells (63). This direct action of metformin on ovarian steroid secretion could secondarily induce an improvement of central obesity, insulin action, and hyperinsulinemia (64).
Menstrual cyclicity improved in half of the subjects during metformin treatment, which is in accordance with the results of recent studies in obese PCOS women (11, 65, 66) and in nonobese adolescents with anovulatory hyperandrogenism (24, 25). However, larger studies are needed to test the real impact of metformin on ovulatory function and fertility in nonobese PCOS women.
Our results confirm that nonobese women with PCOS experience similar hormonal and metabolic improvements during metformin treatment as obese women. However, while metformin mainly affected central obesity and lipid metabolism, with minimal effects on hepatic insulin clearance in obese women, its action seems to be focused mainly on hepatic clearance of insulin and steroid secretion in nonobese subjects. These results suggest either a different pathogenesis of PCOS in nonobese women or the fact that obesity acts as a confounding factor in this disease (21). Although nonobese PCOS women are not hyperinsulinemic in the fasting state, they have incipient compensatory hyperinsulinemia, which can be evidenced only during feeding and by measuring 24-h insulin levels (21). In the present study, a better metabolic and hormonal equilibrium was reached during metformin therapy, confirming that nonobese PCOS subjects could also benefit from this treatment. Because most of the beneficial changes were already observed at 3 months of treatment and at a dosage of 1 g/d, lower doses of metformin than those used in obese PCOS women could be sufficient in nonobese women, as observed also in previous studies (7, 24, 25, 26).
In the present study, an improvement of hirsutism without significant worsening of glucose tolerance during EE-CA treatment was observed. In previous OC studies on healthy and PCOS women, increased glucose and insulin responses during OGTTs, decreased insulin sensitivity, and an association with an increased risk of type 2 diabetes have been found, but results have varied according to the type and dose of progestin (27, 28, 67, 68, 69, 70). In studies involving CA, either a significant decrease of insulin sensitivity and impairment of carbohydrate metabolism (71, 72) or unchanged insulin concentrations and sensitivity (73) have been observed in women with PCOS. Our previous study on obese insulin-resistant PCOS women showed a significant worsening of glucose tolerance with EE-CA (29). In accordance with the present results, a recent study in nonobese women with PCOS has shown no significant change in insulin sensitivity or glucose tolerance during EE-CA treatment, despite a slight nonsignificant increase in BMI (22). However, because nonobese PCOS women have higher WHR and are more insulin resistant than healthy controls (13, 49), at least some of them could benefit from the combination of OC pill and metformin, as shown recently (22). Moreover, in line with previous studies (71, 74, 75, 76, 77), the treatment with EE-CA decreased the S-LDL/HDL ratio and increased the serum triglyceride concentrations. Because these changes have opposite effects on the risk of cardiovascular disease (78, 79, 80, 81), the overall impact of EE-CA treatment on glucose, insulin, and lipid metabolism as regards risks of heart disease remains to be solved in larger follow-up studies.
In the present study, the slight increase of BMI coincided with a significant increase of serum leptin concentrations at 6 months of treatment with EE-CA. Because leptin production correlates with body weight and BMI (82, 83), the increment in leptin levels may be induced by an increase in fat mass in these women. On the other hand, the EE-CA pill by itself could increase serum leptin levels, because circulating leptin concentrations have been shown to be increased by estradiol and estradiol-progesterone combinations in most (83, 84), but not all studies (70).
The treatment with EE-CA significantly increased serum cortisol levels, as observed also in other studies (85, 86). Because serum cortisol binding globulin concentrations have been shown to be increased during the use of OCs (85), it is difficult to conclude whether free cortisol levels change, and therefore the clinical significance of this observation remains unclear.
In conclusion, our results indicate that EE-CA is an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin sensitivity and glucose tolerance have to be taken into consideration also in nonobese subjects. Metformin, via its positive effects on insulin clearance and WHR, improves hyperinsulinemia and hyperandrogenism and offers a good treatment alternative for anovulation in nonobese women with PCOS. Further studies are needed to investigate the real impact of metformin in the treatment of infertility in these women.
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Acknowledgments |
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Footnotes |
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Abbreviations: A, Androstenedione; AUGgluc, glucose area under the curve; AUCins, insulin area under the curve; BMI, body mass index; CA, cyproterone acetate; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; EE, ethinyl estradiol; FAI, free androgen index; FFA, free fatty acid; HDL, high-density lipoprotein; IGFBP, IGF binding protein; IGT, impaired glucose tolerance; OC, oral contraceptives; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; RQ, respiratory quotient; S-LDL, serum low-density lipoprotein; T, testosterone; WHR, waist to hip ratio.
Received June 27, 2002.
Accepted October 10, 2002.
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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]
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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]
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D. Cibula, M. Fanta, J. Vrbikova, S. Stanicka, K. Dvorakova, M. Hill, J. Skrha, J. Zivny, and J. Skrenkova The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients Hum. Reprod., January 1, 2005; 20(1): 180 - 184. [Abstract] [Full Text] [PDF]
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S. Palomba, F. Orio Jr., L. G. Nardo, A. Falbo, T. Russo, D. Corea, P. Doldo, G. Lombardi, A. Tolino, A. Colao, et al. Metformin Administration Versus Laparoscopic Ovarian Diathermy in Clomiphene Citrate-Resistant Women with Polycystic Ovary Syndrome: A Prospective Parallel Randomized Double-Blind Placebo-Controlled Trial J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4801 - 4809. [Abstract] [Full Text] [PDF]
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 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]
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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]
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 M. T. Sheehan Polycystic Ovarian Syndrome: Diagnosis and Management Clin. Med. Res., February 1, 2004; 2(1): 13 - 27. [Abstract] [Full Text] [PDF]
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L. Morin-Papunen, K. Rautio, A. Ruokonen, P. Hedberg, M. Puukka, and J. S. Tapanainen Metformin Reduces Serum C-Reactive Protein Levels in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4649 - 4654. [Abstract] [Full Text] [PDF]
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L. Harborne, R. Fleming, H. Lyall, N. Sattar, and J. Norman Metformin or Antiandrogen in the Treatment of Hirsutism in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4116 - 4123. [Abstract] [Full Text] [PDF]
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A. Cagnacci, A. M. Paoletti, A. Renzi, M. Orru, M. Pilloni, G. B. Melis, and A. Volpe Glucose Metabolism and Insulin Resistance in Women with Polycystic Ovary Syndrome during Therapy with Oral Contraceptives Containing Cyproterone Acetate or Desogestrel J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3621 - 3625. [Abstract] [Full Text] [PDF]
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E. Diamanti-Kandarakis, J.-P. Baillargeon, M. J. Iuorno, D. J. Jakubowicz, and J. E. Nestler A Modern Medical Quandary: Polycystic Ovary Syndrome, Insulin Resistance, and Oral Contraceptive Pills J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1927 - 1932. [Full Text] [PDF]
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) and at 6 months (•) of metformin and EE-CA treatment. *, P < 0.05, compared with the level before treatment.