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Division of Endocrinology, Department of Internal Medicine, and Center for Applied Biomedical Research, S. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy
Address all correspondence and requests for reprints to: Renato Pasquali, M.D., Division of Endocrinology, Department of Internal Medicine, S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. E-mail: renato.pasquali{at}unibo.it.
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Abstract |
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Objective: Our objective was to investigate the long-term effects of these therapies.
Design and Setting: We conducted a prospective, randomized, placebo-controlled trial at a medical center.
Patients: Of 80 overweight-obese women with PCOS, 76 completed the study.
Interventions: Patients were placed on a hypocaloric diet for the first month and then on a hypocaloric diet plus placebo, metformin (850 mg, orally, twice a day), flutamide (250 mg, orally, twice a day), or metformin plus flutamide for the subsequent 12 months (20 subjects in each group).
Main Outcome Measures: We assessed clinical features, computerized tomography measurement of fat distribution, androgens, lipids, and fasting and glucose-stimulated glucose and insulin levels at baseline and after 6 and 12 months of treatment.
Results: After 6 months, compared with placebo, flutamide further decreased visceral/sc fat mass (P = 0.044), androstenedione (P < 0.001), dehydroepiandrosterone sulfate (P < 0.001), and hirsutism score (P < 0.001), whereas metformin further increased frequency of menstruation (P = 0.039). After 12 months, flutamide maintained the effects observed after 6 months on visceral/sc fat mass (P = 0.033) and androstenedione (P < 0.001), whereas it produced an additional decrease in dehydroepiandrosterone sulfate (P = 0.020) and hirsutism score (P = 0.019); metformin further improved the menstrual pattern (P = 0.013). Moreover, after 12 months, flutamide improved more than placebo the menstrual pattern (P = 0.008), glucose-stimulated glucose levels (P = 0.041), insulin sensitivity (P < 0.001), and low-density lipoprotein cholesterol levels (P = 0.003), whereas metformin decreased glucose-stimulated insulin levels (P = 0.014). The combination of the two drugs maintained the specific effect of each of the compounds, without any additive or synergistic effect.
Conclusions: These findings add relevance to the usefulness of metformin and flutamide in the treatment of dieting overweight-obese PCOS women and provide a rationale for targeting different therapeutic options according to the required outcomes in the long term.
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Introduction |
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There is worldwide agreement that dietary-induced weight loss should always represent the first line of therapeutic advice for every obese woman with PCOS (11, 12, 13, 14). On the other hand, in two 6-month studies performed in different overweight-obese PCOS cohorts, we previously showed that more significant beneficial effects can be achieved in this kind of patient by adding metformin (15, 16) or flutamide (16), alone or in combination, to a low-calorie diet. In particular, metformin, the most commonly used insulin sensitizer, produced more favorable outcomes on androgen levels and menses abnormalities (15, 16), and flutamide, a nonsteroidal pure antiandrogen, induced an additional decrease in androgen levels and hirsutism and an improvement in lipid profile (16), whereas the combined treatment produced a further effect in ameliorating hyperandrogenemia and dyslipidemia than either of these drugs in monotherapy (16). Regardless of pharmacological treatment, however, these studies provided evidence that improvement of insulin sensitivity and hyperinsulinemia were mostly dependent on a hypocaloric diet rather than on the specific effect of each compound (15, 16).
Overall, the findings of the aforementioned short- and medium-term studies provided a basis for adapting different therapeutic options to the various clinical and laboratory requirements in overweight-obese PCOS women. However, there are no data from a head-to-head comparison over a longer term of treatment to guide decisions in the choice of treatment.
With this background, we performed a long-term prospective placebo-controlled study in a large group of overweight-obese women with PCOS, by treating them with metformin and flutamide, given alone or in combination, in addition to a hypocaloric diet, for a period of 12 months. The outcomes were to evaluate the impact of these treatments, as compared with placebo, on hyperandrogenism, menses alterations, metabolic abnormalities, and body composition.
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Subjects and Methods |
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A total of 80 women with PCOS were included in the study. Forty of the women were those included in the previous study (16), extending their treatment period for another 6 months, and the other 40 were new patients. All patients were recruited from the Division of Endocrinology, S. Orsola-Malpighi Hospital, University of Bologna, Italy. Inclusion criteria other than PCOS were as follows: reproductive age (range, 18–45 yr), body mass index (BMI) at least 28 kg/m2, and waist circumference at least 88 cm, consistent with an abdominal fat distribution phenotype (17). The diagnosis of PCOS included the following features, according to the Rotterdam consensus (18): chronic anovulation (supported by luteal progesterone measurement) or severe oligomenorrhea/amenorrhea (100%); hirsutism (Ferriman-Gallwey score 
8) (19) or total testosterone (T) levels at least 0.72 ng/ml (2.5 nmol/liter), according to our reference values (100%); and polycystic ovarian morphology at ultrasound (18) (100%). Exclusion criteria included use of any medication or a significant modification in body weight within the previous 3 months or dieting. None of the PCOS women included in the study had hyperprolactinemia; Cushing’s syndrome; late-onset congenital adrenal hyperplasia; thyroid dysfunction; diabetes; or cardiovascular, renal, or liver diseases, based on routine biochemistry and appropriate tests. The protocol was approved by the local ethics committee, and all women gave their informed consent. All women were advised in writing to use nonhormonal contraception throughout the study.
Study design
Treatments. For the first month, patients were placed on a standardized hypocaloric diet containing 20% proteins, 30% lipids, and 50% carbohydrates. All the diets were prescribed by the same dietician attending our division, who calculated the dietary energy composition by subtracting 500 kcal from the usual individual energy intake, evaluated by means of the diet history method and a 3-d recall questionnaire. The final composition of the diets ranged between 1200 and 1400 kcal/d. After the first month and while continuing dietary treatment, PCOS women were randomized to receive placebo (one tablet, orally, twice a day) (n = 20), metformin (850 mg, orally, twice a day) (n = 20), flutamide (250 mg, orally, twice a day) (n = 20), or a combined metformin (850 mg, orally, twice a day) plus flutamide (250 mg, orally, twice a day) regimen (n = 20) for a 12-month treatment course. Therefore, the metformin plus flutamide group took four tablets per day, whereas the other groups took two tablets per day. Metformin, flutamide, and placebo were packaged in similar preparations, and patients were blinded to the treatments. The allocation sequence of the treatments was decided by a third party (A.V.) before the recruitment of the patients by random number tables.
Each woman was given one fresh 1-month package of the drug (active or placebo) at the start of the treatment and again at each monthly visit (L.P.).
Assessment program. All patients underwent clinical, hormonal, and metabolic assessments at baseline, 6 months, and 12 months. A computerized tomography (CT) scan measurement of body fat distribution was also performed at the level of L4–L5 to estimate total (TAT), visceral (VAT), and sc (SAT) adipose tissue areas (16). The frequency of menstruation every 6 months during the study and in the 6 months before the start of the study was also recorded using a calendar compiled by the patients, where they noted the exact dates of the start and the end of each menstrual cycle. This recording was done prospectively for the menstrual cycles that appeared throughout the study, whereas it was done retrospectively for those that appeared within the 6 months before the start of the study. After the first month of hypocaloric diet, women underwent a clinical evaluation only. The clinical examination focused on the evaluation of anthropometric parameters (height, weight, and waist circumference) and hirsutism, by using the Ferriman-Gallwey score (19). Hormonal and metabolic determinations included the evaluation of circulating concentrations of total T, androstenedione (A), dehydroepiandrosterone sulfate (DHEA-S), SHBG, total and high-density lipoprotein (HDL) cholesterol and triglycerides in fasting blood samples, followed by an oral glucose tolerance test (OGTT), in which 75 g glucose (Curvosio, Sclavo, Cinisello Balsamo, Italy) were administered. All blood tests were performed, regardless of the menstrual cycle, at baseline and after 6 and 12 months of study drug. Laboratory tests of renal and liver functions were also assessed at monthly intervals to evaluate the tolerability to the drugs. All these assessments were performed by the same researcher (A.G.), blinded to the treatment, throughout the study.
Furthermore, all women were checked monthly for compliance with both dietary and pharmacological treatments. Compliance with diet was evaluated by the same dietician at each monthly visit, according to a previously defined method providing quantitative information on daily energy intake and macronutrient composition of the diet consumed during the previous month (20). Compliance with the pharmacological treatment was evaluated by the same investigator at each control visit (L.P.), not blinded to the treatment, by counting the number of pills remaining to each woman in the package delivered the month before. Patients developing an alteration in renal and liver laboratory analyses or failing to comply with dietary prescription (as estimated by a 30% excess energy intake in the previous month) or drug treatment were excluded from the study. All subjects were invited to maintain their usual physical activity throughout the study, which was checked monthly by the self-administered questionnaire proposed by Baecke et al. (21).
Assays
Plasma glucose levels were determined by the glucose-oxidase method after blood samples had been obtained. Blood samples were centrifuged immediately, and serum was stored at –20 C and plasma at –80 C until assayed. Biochemical parameters were analyzed from serum, whereas hormones and SHBG were analyzed from plasma. Insulin, total T, A, DHEA-S, SHBG, HDL cholesterol, and triglycerides were measured as previously described (22). Low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald equation (23), whereas free androgen index (FAI) was calculated as the ratio between total T and SHBG, according to Vermeulen et al. (24). To investigate insulin sensitivity, the quantitative insulin-sensitivity check index (QUICKI) and the insulin sensitivity index during the OGTT (ISI) were calculated (25, 26). The intraassay coefficients of variation in our laboratory were 3.0% for insulin, 7.0% for total T, 6.0% for A, 5.9% for DHEA-S, and 6.5% for SHBG.
Statistical analysis
The primary endpoint of the trial was the amelioration of hyperandrogenism. From our previous pilot study, we estimated that the levels of A after 12 months of placebo were 12.7 ± 3.4 nmol/liter, whereas after 12 months of flutamide, they were 8.9 ± 3.5 nmol/liter (16). With a two-tailed test of 
= 0.05 and ß = 0.90, groups of 18 patients each were recruited to yield a statistically significant result. Expecting approximately two dropouts per group, we enrolled a total of 20 patients per group. Similar results were obtained calculating the sample size from T or hirsutism, the other markers of hyperandrogenism in PCOS (18).
Data are reported as mean value ± SD, unless otherwise indicated. The responses of glucose and insulin to the OGTT were analyzed by calculating the area under the curve (AUC) by the trapezoidal method. A one-way ANOVA was applied to compare values among the four groups at each time point (baseline, 6 months, and 12 months), whereas the repeated-measures two-way ANOVA (with one between-subject factor, i.e. groups of treatment; and one within-subject factor, i.e. timing) was performed to estimate the within-group modifications. The simple contrast was used to compare the modifications of each pharmacologically treated group (metformin, flutamide, and metformin plus flutamide) vs. placebo after both 6 and 12 months of treatment. The additional effects [±95% confidence interval (CI)] of each drug to hypocaloric diet (placebo) were also estimated in the entire study population after both 6 and 12 months by a mixed-model repeated-measures three-way ANOVA with two between-subject treatment factors (metformin and flutamide) and one within-subject factor (timing). In addition, the interactions between these factors were also evaluated (which must be added to the single effect of each drug in estimating the additional effect produced by the metformin plus flutamide therapy with respect to placebo). No separate analyses for each treatment were performed, but factors and interactions were evaluated in a unique multifactorial ANOVA for each dependent variable. The Pearson 
2 and the McNemar tests were applied to compare glucose tolerance conditions among the four groups at each time point and to test the modifications in the time intervals within the entire cohort, respectively. Statistical analyses were performed by running the SPSS/PC+ (Chicago, IL) (27) and the BMDP (Berkeley, CA) (28) software packages. Two-tailed P values < 0.05 were used to define statistical significance.
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Results |
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Figure 1
shows the process of patients from recruitment and randomization and through the 12-month treatment program. In the placebo group, one woman was excluded after the first month of treatment for nonattendance at the check-up; in the flutamide group, three women were lost to follow-up because of a mild increment of transaminase levels after 1, 2, and 4 months of drug treatment. In these patients, transaminase levels returned to the normal range a few days after flutamide suspension, without other complications. The cohort available for final statistical analysis therefore included 76 PCOS women, 19 treated with placebo, 20 with metformin, 17 with flutamide, and 20 with metformin plus flutamide. The four different treated groups had a similar energy intake and physical activity score at the beginning (data not shown). Six women who completed the study (two treated with metformin and four with metformin plus flutamide) reported transient abdominal discomfort (abdominal swelling, mild diarrhea, and flatulence) during the first 2 wk of treatment.
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At baseline, there were no significant differences in any parameter among the groups, except for VAT/SAT, which was higher in the metformin vs. the other three groups (Table 1).
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). A similar pattern was found for VAT in the groups treated with metformin or flutamide, whereas it significantly decreased over the first 6 months but remained stable over the last 6 months in those treated with their combination and with placebo (Table 1). The pattern for VAT/SAT was similar in those groups treated with flutamide alone or in combination with metformin (Table 1).
When compared with placebo, the groups treated with metformin, flutamide, and metformin plus flutamide had a similar reduction of body weight, BMI, waist circumference, TAT, SAT, VAT, and VAT/SAT values after 6 months (Fig. 2 for VAT). After 12 months, a greater reduction in TAT (P = 0.001), SAT (P = 0.003), and VAT (P = 0.049) (Fig. 2 for VAT) values was, however, observed in the flutamide group only.
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At baseline, there were no significant differences in any parameter among the groups (Table 2). Total T decreased after 6 months and remained stable until the end of the study in all of the groups (Table 2). A similar pattern was detectable for FAI, except in the placebo group, in which no change over the study was observed (Table 2). Levels of A significantly decreased only after 12 months in the placebo and metformin groups, whereas in those taking flutamide alone or in combination, an earlier significant fall in A levels occurred (Table 2). These latter groups were also characterized by an early significant decrease in DHEA-S and an increase in SHBG, which reached significance after 12 months of treatment (Table 2).
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for FAI, A, and DHEA-S). Conversely, no significant difference was observed in any parameter in the group treated with metformin (Fig. 2 for FAI, A, and DHEA-S). Glucose, insulin, and insulin resistance indexes
At baseline, fasting glucose and insulin concentrations and glucoseAUC were similar among the groups (Table 3). Conversely, insulinAUC was significantly higher in the metformin group, and QUICKI and ISI were lower in the placebo and metformin groups with respect to the others (Table 3).
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). Insulin and insulinAUC significantly decreased in all the groups during the first 6-month period; during the following 6 months, an additional significant reduction in fasting insulin was observed in all the groups except for placebo, whereas no additional significant changes in insulinAUC were found (Table 3). QUICKI and ISI significantly improved after 6 months in the placebo group, without any additional change thereafter; on the contrary, values progressively and significantly improved over the entire period of the study in the other groups (Table 3).
When compared with placebo, changes in fasting glucose and insulin and in glucoseAUC, QUICKI, and ISI did not significantly differ after 6 months in the other three groups (Fig. 2 for ISI). Conversely, modification of insulinAUC was significantly greater in the group taking metformin (P = 0.019) (Fig. 2). After 12 months, a greater decrease in insulinAUC persisted in the metformin group (P = 0.009), whereas an additional increase in ISI occurred in the flutamide (P = 0.030) and metformin plus flutamide (P < 0.001) groups (Fig. 2). A similar additional decrease of glucoseAUC occurred in the last 6 months of treatment in the group treated with metformin plus flutamide (P = 0.030).
Normal glucose tolerance (NGT), impaired fasting glucose (IFG), and/or impaired glucose tolerance (IGT) were similarly expressed among the groups at each time point, and prevalence rates of NGT similarly increased, whereas those of IFG and/or IGT similarly decreased in all groups throughout the study (Table 4).
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At baseline, no significant differences were observed among the groups (Table 3). LDL cholesterol significantly decreased after 6 months and remained stable until the end of the study in the metformin plus flutamide group, whereas it significantly decreased in the groups treated with metformin or flutamide only after 12 months (Table 3). HDL cholesterol significantly increased in all the groups after 12 months, whereas triglycerides did not change at any time in any group (Table 3).
Compared with placebo, none of the active treated groups differed in changes of lipid concentrations after 6 months of treatment (Fig. 2 for LDL cholesterol). A greater reduction in LDL cholesterol levels was, however, found after 12 months in the metformin plus flutamide group (P = 0.001) (Fig. 2).
Clinical parameters
At baseline, hirsutism score and frequency of menstruation were comparable among the groups (Table 1). Hirsutism score significantly decreased and the frequency of menstruation significantly increased in all the groups over the first 6 months of treatment (Table 1). Over the last 6 months, hirsutism further decreased in the flutamide and metformin plus flutamide groups, whereas menstrual pattern further improved in the metformin plus flutamide group (Table 1).
When compared with placebo, hirsutism decreased significantly more in the flutamide and the metformin plus flutamide groups after both 6 and 12 months of treatment (P < 0.001), with a significant additional later decrease (P = 0.013) in the flutamide group (Fig. 2). Menstrual pattern improved more in the metformin and metformin plus flutamide groups after 6 months (P = 0.031 in the metformin and P = 0.044 in the metformin plus flutamide group) and 12 months (P = 0.003 in the metformin and P < 0.001 in the metformin plus flutamide group) of treatment, with a significant additional late improvement (P = 0.001) in the metformin plus flutamide group (Fig. 2).
Estimate of the effect attributable to metformin and flutamide and to their interaction in the entire study population
Table 5 reports the additive effect of each drug to hypocaloric diet (placebo) and the specific effect attributable to their interaction during the combined therapy in the entire study population after 6 and 12 months (for details, refer to Statistical analysis). Drugs had no specific effects on body weight, waist circumference, or VAT at any time. Flutamide, however, had a significant additive effect in reducing TAT and SAT after 12 months and in decreasing VAT/SAT after both 6 and 12 months of treatment. A significant additive effect in decreasing hirsutism and in increasing frequency of menstruation was observed after 6 months and, furthermore, after 12 months of treatment with flutamide and metformin, respectively. Interestingly, flutamide had a significant additive effect in increasing frequency of menstruation after 12 months. Both drugs had no specific effects on total T, FAI, and SHBG, whereas a specific and significant effect of flutamide in decreasing A and DHEA-S levels was observed after both 6 and 12 months of treatment, with a progressive effect on DHEA-S reduction. After 12 months, flutamide also had a specific effect in decreasing glucoseAUC and in improving ISI and LDL cholesterol levels, whereas an additive effect of metformin in decreasing insulinAUC was observed. The coadministration of the two drugs combined the specific effects of each of them, without any additional effect derived from their interaction.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hypocaloric diet has been widely proved to be an effective treatment of overweight or obese PCOS women (2, 3, 15, 16, 29). The findings of this study confirm previous results and further demonstrate that restricted energy intake, as well as favoring weight loss and decreasing adipose tissue, significantly improves insulin resistance, hyperinsulinemia, and glucose tolerance, reduces hyperandrogenemia, and exerts a significant, although modest, favorable effect on hirsutism and menstrual pattern, even after a medium period of treatment (i.e. 6 months). In addition, we have shown that even if body weight reduction did not continue over the latter part of the study, these benefits persisted overall, whereas others (HDL cholesterol) further ameliorated later in time. This definitively highlights the finding that the maintenance of body weight lost in the first months of hypocaloric diet administration may have a great importance in the long-term treatment of overweight-obese PCOS women, in accordance with what has already been demonstrated in large studies performed in subjects with simple obesity (30, 31).
In the last 15 yr, several randomized controlled studies have demonstrated that metformin significantly improves menses alterations, ovulatory rates, and hormonal and metabolic derangements in PCOS women, particularly in those with obesity but also in insulin-resistant, normal-weight ones (32, 33, 34). However, the majority of these studies were performed by administering metformin without restricting energy intake, which represents an inadequate way to treat PCOS when excess body weight is present. In two previous medium-term (6-month) studies performed in overweight-obese PCOS women (15, 16), we showed an additional increment in frequency of menstruation, without any additive amelioration of insulin resistance and insulin levels, when metformin was added to a low-calorie diet. Here, we have reported that the effectiveness of metformin on frequency of menstruation over the low-calorie diet tends to be progressively more pronounced as time goes on, being, however, associated with a significant reduction of glucose-stimulated insulin levels mainly after a long-term treatment. These results support the concept that the improvement of hyperinsulinemia may represent an important mechanism by which metformin may favor the amelioration of menstrual pattern in overweight-obese PCOS women but also suggests that other circulating or local factors controlling the ovarian function are probably involved (35). However, the higher baseline insulin responsiveness to glucose load and the higher insulin resistance state observed in the metformin-treated group with respect to the others should be taken into account for the correct interpretation of these data. Moghetti et al. (6) demonstrated in fact that pretreatment high plasma insulin levels are independent predictors of clinical efficacy of metformin treatment in obese PCOS women, particularly on the amelioration of menstrual abnormalities.
The absent additional benefit of metformin over diet on androgen levels found in this study is in accordance with a previous double-blind study comparing the effects of a 4-month low-calorie diet vs. diet plus metformin in obese hirsute women performed by Crave et al. (36). Unfortunately, that study was not specifically designed to recruit women with PCOS, and the large majority of patients had regular menses.
This study also confirms and expands previous results found by our group (16) about the medium-term effect of flutamide, given alone or in combination with metformin in low-calorie dieting overweight-obese PCOS women, in decreasing androgen concentrations (A and DHEA-S) and in improving hirsutism. Interestingly, these effects appeared to progressively increase over time, thus suggesting that flutamide may represent a promising compound in treating the hyperandrogenism of PCOS women in the long run.
In addition, flutamide significantly decreased visceral fat, glucose-stimulated glucose levels, and LDL cholesterol levels and improved insulin sensitivity, therefore favoring the achievement of a more healthy metabolic profile, particularly in the long term. Moreover, after 12 months of treatment, we found that flutamide significantly increased frequency of menstruation. This last effect should be considered a consequence of the reduction of excess androgen secretion or blockade of central androgen action with consequent restoration of the sensitivity of the GnRH pulse generator to estradiol and progesterone, as suggested by Eagleson et al. (9).
Overall, these findings suggest that antiandrogens should be considered in the long-term treatment of women with PCOS and, indirectly, support a primary role of androgen excess in the pathophysiology of this disorder (37). It has been widely demonstrated that androgen excess in women is closely related to the central type of body fat distribution (38) and that androgen administration to postmenopausal women leads to increased visceral fat depots (39). The long-term ability of flutamide to reduce body fat, particularly visceral fat, strongly supports the significant role of androgens in the regulation of fat metabolism and differentiation, according to sexes (40). The role of androgens in determining insulin resistance is supported by studies performed in both rats and humans. In particular, the long-term exposure of castrated females to testosterone led to insulin resistance by increasing the number of less insulin-sensitive type IIb skeletal muscle fibers (41) and by inhibiting muscle glycogen synthase activity (42). Moreover, prolonged T administration to female-to-male transsexuals resulted in a significant decrease of insulin-mediated glucose uptake in euglycemic clamp studies (43). Whether antiandrogens may improve insulin sensitivity in PCOS is still a debatable issue, with previous short-/medium-term studies having reported both positive (44) and negative (16, 45) results. However, our data clearly indicate the possibility that long-term treatment with antiandrogens is necessary to achieve a significant improvement of insulin sensitivity in overweight-obese PCOS women, therefore justifying the negative results described in most of the short-/medium-term studies performed so far.
In conclusion, the findings of the present study confirm that lifestyle intervention has a fundamental role in the long-term treatment of overweight-obese PCOS women. In addition, they provide another rationale for adding metformin and flutamide according to the required outcomes. In particular, metformin seems to be indicated when the improvement of hyperinsulinemia and of menstrual pattern are the prevalent targets of the treatment, whereas flutamide can be administered to counteract hyperandrogenism and even to improve metabolic derangement, including insulin resistance and lipid abnormalities. Finally, the combination of the two drugs gives the opportunity to combine the positive effect of each of the compounds. Additional studies are needed to evaluate whether these benefits can be achieved with even lower antiandrogen dosages.
No conclusion about the effect of the different treatments on ovulation can be drawn from this study because no specific measurements were performed.
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Acknowledgments |
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Footnotes |
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First Published Online July 25, 2006
Abbreviations: A, Androstenedione; AUC, area under the curve; BMI, body mass index; CI, confidence interval; CT, computed tomography; DHEA-S, dehydroepiandrosterone sulfate; FAI, free androgen index; HDL, high-density lipoprotein; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ISI, insulin sensitivity index during the OGTT; LDL, low-density lipoprotein; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; QUICKI, quantitative insulin-sensitivity check index; SAT, sc adipose tissue; T, testosterone; TAT, total adipose tissue; VAT, visceral adipose tissue.
Received October 11, 2005.
Accepted July 13, 2006.
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| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) of clinical, hormonal, and biochemical data at 6 months (white bars) and at 12 months (black bars) in the groups treated with placebo (PLAC), metformin (MET), flutamide (FLUT), and metformin plus flutamide (MET+FLUT). a, P < 0.05; b, P < 0.01; and c, P < 0.001 refer to the differences in changes of the parameters from baseline to 6 months and from baseline to 12 months between the groups treated with MET, FLUT, or MET+FLUT and PLAC. 
, P < 0.001 refer to the differences in changes of the parameters from 6 to 12 months between the groups treated with MET, FLUT, or MET+FLUT and PLAC. Data are shown as mean ± SEM.