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Original Studies |
Endocrine Unit (R.P., A.G., D.B., V.V., L.G., D.C., S.F., A.M.M.-L.), Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital; and Department of Obstetric and Gynecology, Reproductive Endocrinology Center (G.E.C., M.F.), University of Bologna, 40138 Bologna, Italy
Address correspondence and requests for reprints to: Renato Pasquali, M.D., Endocrine Unit, Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138, Bologna, Italy. E-mail: rpasqual{at}almadns.unibo.it
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Abstract |
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During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance; and 2 PCOS women, both treated with metformin, were also excluded because they became pregnant. Therefore, the women cohort available for final statistical analysis included 18 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo).
The treatment was well tolerated. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. Baseline anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups, without any significant effect on CT scan parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in the waist-to-hip ratio values were similar in PCOS women and controls, regardless of pharmacological treatment. Metformin treatment significantly decreased SAT values in both PCOS and control groups, although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment. On the contrary, visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups, but only in the former was the effect of metformin treatment significantly higher than that of placebo.
Fasting insulin significantly decreased in both PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin. Neither metformin or placebo significantly modified the levels of LH, FSH, dehydroepiandrosterone sulphate, and progesterone in any group, whereas testosterone concentrations decreased only in PCOS women treated with metformin. SHBG concentrations remained unchanged in all PCOS women; whereas in the control group, they significantly increased after both metformin and placebo. Leptin levels decreased only during metformin treatment in both PCOS and control groups.
In summary, this study shows that, in PCOS women with abdominal obesity, long-term treatment with metformin added to hypocaloric diet induced, in comparison with placebo, a greater reduction of body weight and abdominal fat, particularly the visceral depots, and a more consistent decrease of serum insulin, testosterone, and leptin concentrations. These changes were associated with a more significant improvement of hirsutism and menses abnormalities. Moreover, the effects on body weight, insulin, and leptin were similar to those observed in the group of comparable abdominally obese controls, in whom, however, a more pronounced reduction of sc fat in the abdominal region and an increase of SHBG concentrations were found. These findings, therefore, indicate that hyperinsulinemia and abdominal obesity may have complementary effects in the pathogenesis of PCOS.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Dietary-induced weight loss is usually followed by reduced hyperandrogenism and hyperinsulinemia and improved clinical status (such as fewer menses abnormalities, less hirsutism, and increased fertility rate) in many obese women with PCOS (17, 18, 19). On the other hand, with the exception of one study (20), the administration of insulin-lowering drugs, such as diazoxide (21), metformin (6, 22, 23), troglitazone (24), and (more recently) D-chito-inositol (25), has been proved to obtain the same results, regardless of significant changes in body weight, thus emphasizing the role of hyperinsulinemia in the pathophysiology of PCOS. Whether these effects may be mediated, at least in part, by selective reduction of visceral fat is still unknown. In addition, studies performed so far in obese PCOS women failed to investigate the effect of long-term hypocaloric dieting with or without the association of insulin sensitizers on body composition and fat distribution.
Therefore, we carried out this study to evaluate the effects of combined hypocaloric diet and metformin, an insulin-sensitizer agent, on body weight and fat distribution in a group of PCOS women with the abdominal obesity phenotype. The fasting insulin and glucose-stimulated insulin levels and androgen and leptin blood concentrations were also investigated. Moreover, to evaluate whether the effects of such a treatment were specifically conditioned by the presence of PCOS or by the presence of abdominal obesity, a control group of women, comparable for age and pattern of body fat distribution but without PCOS, was also investigated.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A group of 20 women with PCOS and a group of 20 controls, comparable for age and weight, were included in the study. They were recruited as outpatients attending the Endocrine Unit of the Department of Internal Medicine and Gastroenterology of the S. Orsola-Malpighi Hospital of Bologna. All PCOS and control women were obese, with body mass index (BMI; kg/m2) values greater than 28, and had abdominal body fat distribution defined by waist-to-hip ratio (WHR) values greater than 0.80 (26). The diagnosis of PCOS was made according to the presence of oligomenorrhea (less than four cycles in the last 6 months) or amenorrhea (no menses in the last 6 months) and hyperandrogenism, defined by supranormal total and free T concentrations, according to normal reference values in our laboratory (27). All women with PCOS had ovarian ultrasonic findings consistent with the diagnosis (28). None of the PCOS or control women had thyroid dysfunction, type II diabetes, or concomitant cardiovascular, renal, and liver dysfunction, based on clinical examination and routine laboratory findings. Other causes of hyperandrogenisms, such as Cushing syndrome and disease and congenital adrenal hyperplasia, were excluded by normal cortisol suppression after an overnight 1-mg dexamethasone test and normal fasting and stimulated (250 mg Synacthen iv) 17-hydroxyprogesterone concentrations. All PCOS women also had normal PRL levels. None of the PCOS or control women had taken any medication for at least 3 months before the study, nor were they dieting. Women of the control group had regular monthly menses and no clinical or laboratory evidence of androgen excess.
The protocol was approved by the Ethics Committee of S. Orsola-Malpighi Hospital, and all women gave their informed consent.
Anthropometry and measurement of body fat distribution
Body height was measured (without shoes) to the nearest 0.5 cm, and body weight (without clothes). According to the recommendation of the World Health Organization (29), waist circumference was obtained as the minimum value between the iliac crest and the lateral costal margin, whereas hip circumference was determined as the maximum value over the buttocks, using a 1-cm-wide metal measuring tape. Body fat distribution was also defined by a standardized measurement of body fat at the L4-L5 level, by computerized tomography (CT), which was performed on a scanner (Siemens, Erlangen, Germany). Total adipose tissue area (TAT), visceral adipose tissue area (VAT), and sc adipose tissue area (SAT) were calculated as previously described (30). Previous studies (reviewed in Ref. 31) have shown that visceral fat areas from a single scan taken at the level L4-L5 were highly correlated to total visceral fat (r > 95%), measured by multiple CT scans.
Protocol study
At baseline, PCOS women were studied within the first 10 days after the last menstruation if they had mild oligomenorrhea, or randomly if they had severe oligomenorrhea or amenorrhea, whereas all control women were studied during the early follicular phase of the menstrual cycle, except 2 women who were studied during the luteal phase. All women were following their usual diet, providing at least 250–300 g of carbohydrates were ingested. Blood samples for baseline hormone were drawn in the morning, at 0800–0830 h, after an overnight fast. An oral glucose tolerance test (OGTT) (75 g Curvosio, Sclavo, Cinisello Balsamo, Italy) was then performed, and blood samples were collected after 30, 60, 90, 120, and 180 min for glucose determination and after 60, 120, and 180 min for insulin determination. In the afternoon of the same day, the CT scans were performed. The day after, all women were then placed, for a month, on a standardized hypocaloric diet consisting of 1200–1400 kcal daily and containing 50% carbohydrates, 30% total lipids, and 20% proteins. The women returned after 1 month for a checkup, when body weight and body circumferences were newly measured and the CT scan was repeated. Apart from anthropometric and CT scan parameters, the OGTT and sex hormone blood samples were not performed after the first month of dietary therapy. In fact, it is well known that early reduction in body weight may mainly reflect a large loss of body water and that the changes in metabolic and hormonal parameters observed in these conditions may be caused by the effects of undernutrition rather than by changes in body composition (32). While continuing dietary treatment, PCOS women and obese controls were subsequently placed, in a random order, on metformin (Laboratori Guidotti Spa, Pisa, Italy; 850 mg/os, twice daily) (12 PCOS and 8 controls, respectively) or placebo (8 PCOS and 12 controls, respectively), according to a double-blind design, for the following 6 months. The randomization schedule was generated in blocks of 4, and the drug and placebo were packaged and labeled according to subject number. Dietary and pharmacological treatment were maintained for the following 6 months, during which the women were regularly checked, at monthly intervals, to evaluate compliance with the diet and pharmacological treatment and any side effects. Each woman was given 1 fresh 1-month pack of metformin or placebo at the start of the treatment and again at each monthly visit. Compliance with the treatment was evaluated by counting the number of pills remaining to each woman at each control visit. At the end of the trial, the women returned for the final study, which included the same protocol performed at baseline. In this case, blood testing was performed, regardless of the menstrual cycle, in both the women with PCOS and the controls. During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance with the diet. Another 2 PCOS women, both treated with metformin, were also excluded from the trial because they became pregnant while they were on month 1 and 4 of the treatment, respectively. Therefore, the women cohort available for final statistical analysis included 18 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo).
Assays
Plasma glucose levels were determined by the glucose-oxidase method immediately after blood samples had been obtained. Blood samples for hormones were centrifuged immediately, and serum was stored at -20 C° until assayed. To avoid variation between assays, all the samples from an individual woman were analyzed in duplicate in a single assay for each hormone. Insulin and C-peptide were measured by reagents purchased from Eiken Chemical Corporation (Tokyo, Japan) and Sclavo (Cinisello Balsamo, Italy), respectively. Gonadotropin LH and FSH, T, dehydroepiandrosterone sulphate (DHEA-S), estradiol (E2), progesterone (P), SHBG, and leptin levels were measured as previously described (27, 30, 33). The intraassay coefficient of variation in our laboratory was 3.0% for insulin, 3.7% for C-peptide, 7.0% for T, 5.9% for DHEA-S, 5.6% for E2, 4.1% for P, 6.5% for SHBG, 3.0% for leptin, 4.8% for LH, and 1.9% for FSH.
Statistical analysis
Results are reported as the mean values ± SD, unless otherwise indicated. The response of glucose, insulin, and C-peptide to the OGTT was analyzed by calculating the (AUC) by the trapezoidal method. Normal distribution and homoscedasticity of continuous variables were tested by means of the Kolmogorov-Sminorv (34) and the Levene tests (35). Variables that did not fulfill these tests were log-transformed before analysis. To avoid multiple comparisons, the data at the different times of the study were evaluated by means of two-way ANOVA, applying a within-treatment and group design, while the within-subject ANOVA, with the same design, was used to compare the modifications observed during the course of the study. The scores of clinical parameters were analyzed by means of the Wilcoxon matched-pairs and the Mann-Whitney tests (34). Statistical evaluations were performed by running the SPSS, Inc.(Chicago, IL)/PC+ software package on a personal computer (36). Two-tailed P values less than 0.05 were used to define statistical significance.
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Results |
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The treatment was well tolerated by all women. No women suspended the therapy because of side effects, although some of them (one PCOS and one control woman, both treated with metformin) experienced transient mild diarrhea and flatulence during the first 2 weeks of treatment.
Clinical parameters
At baseline, 13 PCOS women were hirsute (9 in the metformin group and 4 in the placebo group). During treatment, the Ferriman-Gallway score decreased significantly in those treated with metformin (basal, 14.8 ± 7.5; after, 12.9 ±.7.6; P < 0.05) but not in those taking placebo [basal, 11.5 ± 10.7; after, 10.3 ± 10.5; P = NS (not significant)]. None of the control women were hirsute.
At baseline, nine PCOS and six control women had acanthosis nigricans. Although several of them who were included in both treatments improved, no significant difference was found in either group between metformin and placebo.
Both PCOS groups improved the frequency of their menstrual cycles (metformin group: basal, 1.2 ± 1.6; after, 4.7 ± 2.1; P < 0.01) (placebo group: basal, 1.3 ± 1.5; after, 3.5 ± 2.3; P < 0.05), but the effects of metformin were significantly higher than those of placebo (P < 0.05).
Anthropometry and fat distribution
Baseline anthropometric and CT scan parameters and their changes
during treatment are reported in Table 1
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In basal conditions, there was no difference in any of them between
PCOS and controls within each group, between women treated with
metformin or placebo. Changes in body weight and BMI during the first
month of hypocaloric dieting were similar in PCOS and control women and
were not significantly different in subgroups treated with metformin or
placebo. However, during the 6-month pharmacological treatment, both
PCOS and controls treated with metformin similarly and significantly
decreased body weight (PCOS, P < 0.05; controls,
P < 0.001) and BMI (PCOS, P < 0.05;
controls, P < 0.01) more than women treated with
placebo. In all groups, there was a significant reduction in waist
circumference after the first month of hypocaloric diet. Metformin
therapy further significantly reduced waist circumference values during
the 6-month treatment in both PCOS and controls, but only in the latter
was a significant difference vs. placebo treatment found
(P < 0.05). On the contrary, metformin and placebo
induced a similar decrease in hip circumference in both PCOS and
control women. Neither grouping nor treatment had a significant effect
on WHR values.
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Glucose, insulin, and C-peptide
Fasting and glucose-stimulated values of glucose, insulin,
and C-peptide before and at the end of the study are reported in Table 2. At baseline, there were no differences
in any parameters between PCOS and controls or between metformin and
placebo within each subgroup.
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At baseline, mean fasting insulin levels and insulinAUC tended to be higher, although not significantly, in PCOS than in controls. In both groups, however, they significantly decreased during the treatment, regardless of therapy. On the contrary, insulinAUC significantly decreased only in the PCOS group and in the controls treated with metformin, whereas no significant variation was found in the placebo-treated groups. As a consequence, changes in insulinAUC after metformin seemed to be higher than those observed after placebo, in both PCOS (P < 0.06) and control women (P < 0.01).
Fasting C-peptide decreased significantly only in the metformin-treated PCOS group. Conversely, C-peptideAUC significantly decreased in both PCOS and controls treated with metformin, but not in the placebo-treated groups. However, within each group, no significant differences in C-peptideAUC values were found between metformin and placebo treatment.
Sex hormones and SHBG
Baseline and posttreatment sex hormone and SHBG values are
reported in Table 3. At baseline, PCOS
women had significantly higher LH and T levels than controls, whereas
no significant difference was found in FSH, DHEA-S, and E2 values.
However, because, in two control women included in the placebo group,
baseline blood samples were collected in the luteal phase, this group
had significantly higher P levels than the PCOS group treated with
placebo.
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Treatment did not significantly modify SHBG levels in PCOS groups; whereas, in the controls, SHBG significantly increased after both metformin and placebo. Therefore, posttreatment SHBG levels were significantly higher in controls than in PCOS women, regardless of treatment. E2 concentrations increased significantly only in the metformin-treated PCOS women, without any changes in those taking placebo and in the control groups. However, no significant difference was present in the PCOS group between metformin and placebo treatment.
Leptin
There were no differences in baseline leptin concentrations
between PCOS women and controls. Both PCOS women and controls treated
with metformin significantly decreased their leptin concentrations,
whereas no significant variation after placebo was found in either
group (Fig. 1). However, in both PCOS
women and controls, mean changes observed during metformin or placebo
were not significantly different.
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Discussion |
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What the role of a reduction in adipose tissue, particularly visceral fat, is in determining these modifications is not yet clearly established. Our study was specifically conducted to determine whether the long-term administration of metformin, which can improve insulin resistance and reduce hyperinsulinemia, may have effects that supplement hypocaloric diet in reducing circulating insulin and androgen blood levels in obese PCOS women and to investigate whether these effects may be related, at least in part, to changes in body weight and fat distribution. To avoid confounding factors, only PCOS women with the abdominal obesity phenotype were included in the study, together with an age- and fat distribution-matched group of women with obesity but without PCOS. Both conditions are, in fact, associated with moderate-to-severe hyperinsulinemia and insulin resistance (1, 37). An apparent limitation of the study is that we did perform hormone blood levels and OGTT after 1 month of hypocaloric dieting. On the other hand, this was done to avoid the counterproductive effects of hypocaloric diet on hormones and metabolism. However, as was to be expected, the loss of weight after such a short time was similar in the PCOS women and in controls, regardless of the pharmacological treatment. This makes it unlikely that not having repeated these measurements after 1 month lead-in period could have affected the interpretation of the results. However, even if the above is taken into account, our data indicate that obese PCOS women and obese controls lost more weight while on metformin than on placebo. Compared with other studies, the weight loss in PCOS women and controls treated with metformin seems to have been greater than expected. In effect, our findings are in agreement with those reported by Crave et al. (38), who treated a group of obese hirsute PCOS women with hypocaloric diet (1500 kcal/day) and metformin (1500 mg/day) or placebo for 4 months and found a tendency toward greater weight loss in the metformin-treated group than in those receiving placebo. Unfortunately, any further comparison regarding the effects of metformin on weight loss in PCOS is difficult because, in most of the studies carried out (6, 20, 22, 23), metformin was administered without dietary restriction and, therefore, changes in body weight were negligible. It is also important to consider that, in our study, we only included PCOS and control women with abdominal obesity, whereas all other cited studies examined obese PCOS women regardless of their body fat distribution pattern. Because, during hypocaloric dieting, women with the abdominal obesity phenotype respond better than those with the peripheral (or sc) phenotype (39), it could have been expected that, when metformin is combined with a hypocaloric diet, the weight loss could be greater than that observed in the majority of studies carried out in nonselected obese subjects (with or without PCOS). In addition, metformin therapy favored a greater reduction of the waist circumference in both groups, which suggests a significant modification of the pattern of fat distribution, particularly at the abdominal level. However, whereas obese PCOS lost significantly more VAT in the abdomen area during metformin than during placebo treatment, without any significant difference in changes of SAT, the opposite was observed in the control obese group. These findings, therefore, suggest disparate effects of metformin added to the diet on visceral fat in PCOS, with respect to control women, in spite of the fact that they were characterized by similar obesity phenotype. They clearly seem to be related to changes in the hormonal environment that occurred during treatment in PCOS and in controls.
As expected, treatment significantly reduced fasting insulin levels; but, unlike placebo, metformin significantly decreased insulin and C-peptide response to oral glucose administration, which indicates a contemporary improvement of both insulin resistance and ß-cell function. The extent of these effects was similar in PCOS and control metformin-treated women, which means that the responsiveness of the insulin-glucose system was not affected by the presence of PCOS per se, but rather by the reduction of abdominal obesity.
The pathogenetic role of obesity and body fat distribution in PCOS is still a matter of intensive debate. Available data seem to support the concept that PCOS and obesity may have an additive effect, or a synergistic, negative impact on insulin sensitivity (1). However, in a study performed in a cohort of normal-weight and obese women with and without PCOS and different patterns of body fat distribution, we previously showed that hyperinsulinemia was more consistently correlated with abdominal fat distribution, regardless of the presence of PCOS (40). In addition, others found that women with PCOS may not be insulin-resistant in the absence of increased abdominal fatness, in spite of significant hyperandrogenism (3). In addition, our present and previous intervention data (41) indicate that hyperinsulinemia and insulin resistance may be largely reversible with reduction or normalization of abdominal fat depots. Therefore, it is hypothesized that abdominal (visceral) fatness may have a dominant role in determining these abnormalities in most women with PCOS, regardless of other factors, including genetic predisposition (1).
A reduction in serum T levels occurred only in the metformin-treated PCOS group but not in the control group or in the PCOS taking placebo in addition to hypocaloric diet. Some previous studies had, in fact, shown that weight reduction obtained with hypocaloric diet alone was associated with a significant decrease in serum T levels (17, 18, 19). At variance, Crave et al. (38) found no difference between metformin and placebo added to hypocaloric diet after 4 months treatment in a group of obese hirsute women, most of whom probably had PCOS. The most likely explanation seems to be that all these studies included PCOS women based on the presence of obesity but with a wide range of body fat distribution. Contrary to what is reported by other studies (19, 21, 38), we found no significant variations in SHBG concentrations in PCOS women, whereas they were significantly increased in both metformin- and placebo-treated control women. The lack of SHBG increase in the PCOS group, particularly in those treated with metformin, was an unexpected finding. On the other hand, the fact that SHBG levels increased in the controls (both during metformin and placebo treatment) makes it improbable that the data depend on the size of the sample, unreliable assay systems, or statistical inadequacy. Other factors may probably be involved. In fact, at variance with previous studies, all women included in the study had abdominal obesity, a condition always associated with reduced SHBG concentrations (12). However, among PCOS women, lowered SHBG concentrations can also be found in those with the peripheral obesity phenotype, regardless of whether they may be relatively less hyperandrogenic and hyperinsulinemic, with respect to those with abdominal obesity (14). Moreover, the fact that approximately half the PCOS women were still relatively hyperinsulinemic and hyperandrogenic, although sia mean values of both T and insulin (fasting and glucose-stimulated) were significantly lower during treatment, particularly in the metformin-treated group, may further explain the nonincrease of the SHBG concentrations during treatment. Therefore, further studies are needed in this area, focusing on the effects of weight loss and insulin-lowering drugs in PCOS women according to specific obesity phenotype.
Finally, we found a significant effect of metformin treatment on leptin levels, which was identical in PCOS women and in controls. Because leptin levels are dependent on the amount of total body fat (42), these findings can be explained by the greater weight reduction found in both groups treated with metformin, compared with those treated with placebo. In addition, they may be dependent on the greater reduction of insulin levels induced by the metformin treatment. In fact, metformin administration has been found to decrease serum leptin in obese PCOS women, even in the absence of changes in body weight (43). Therefore, these findings confirm the regulatory role of insulin on leptin synthesis and secretion (44).
In summary, this study shows that, in PCOS women with abdominal obesity, long-term treatment with metformin, added to hypocaloric diet, induced (in comparison with placebo) a greater reduction of body weight and visceral fat and a more consistent decrease of serum insulin, T, and leptin concentrations. These changes were associated with a more significant improvement of menses abnormalities. The effects on body weight, insulin, and leptin were similar to those observed in the group of comparable abdominally obese controls in whom, however, a more pronounced reduction of sc fat in the abdominal region and an increase of SHBG concentrations were found. These findings, therefore, indicate that hyperinsulinemia and abdominal obesity may have complementary effects in the pathogenesis of PCOS.
Received July 27, 1999.
Revised November 23, 1999.
Revised January 20, 2000.
Revised April 20, 2000.
Accepted April 24, 2000.
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S. Eisenhardt, N. Schwarzmann, V. Henschel, A. Germeyer, M. von Wolff, A. Hamann, and T. Strowitzki Early Effects of Metformin in Women with Polycystic Ovary Syndrome: A Prospective Randomized, Double-Blind, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 946 - 952. [Abstract] [Full Text] [PDF]
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M. Mohlig, J. Spranger, M. Ristow, A. F H Pfeiffer, T. Schill, H. W Schlosser, L. Moltz, G. Brabant, and C. Schofl Predictors of abnormal glucose metabolism in women with polycystic ovary syndrome Eur. J. Endocrinol., February 1, 2006; 154(2): 295 - 301. [Abstract] [Full Text] [PDF]
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T. Tang, J. Glanville, C. J. Hayden, D. White, J. H. Barth, and A. H. Balen Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study Hum. Reprod., January 1, 2006; 21(1): 80 - 89. [Abstract] [Full Text] [PDF]
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N. A. Cataldo, F. Abbasi, T. L. McLaughlin, M. Basina, P. Y. Fechner, L. C. Giudice, and G. M. Reaven Metabolic and ovarian effects of rosiglitazone treatment for 12 weeks in insulin-resistant women with polycystic ovary syndrome Hum. Reprod., January 1, 2006; 21(1): 109 - 120. [Abstract] [Full Text] [PDF]
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A. P. M. Viljanen, K. A. Virtanen, M. J. Jarvisalo, K. Hallsten, R. Parkkola, T. Ronnemaa, F. Lonnqvist, P. Iozzo, E. Ferrannini, and P. Nuutila Rosiglitazone Treatment Increases Subcutaneous Adipose Tissue Glucose Uptake in Parallel with Perfusion in Patients with Type 2 Diabetes: A Double-Blind, Randomized Study with Metformin J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6523 - 6528. [Abstract] [Full Text] [PDF]
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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]
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 K. M. Levri, E. Slaymaker, A. Last, J. Yeh, J. Ference, F. D'Amico, and S. A. Wilson Metformin as Treatment for Overweight and Obese Adults: A Systematic Review Ann. Fam. Med, September 1, 2005; 3(5): 457 - 461. [Abstract] [Full Text] [PDF]
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I.A.A. Penna, P.R.B. Canella, R.M. Reis, M.F. Silva de Sa, and R.A. Ferriani Acarbose in obese patients with polycystic ovarian syndrome: a double-blind, randomized, placebo-controlled study Hum. Reprod., September 1, 2005; 20(9): 2396 - 2401. [Abstract] [Full Text] [PDF]
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S. A.R. Doi, M. Al-Zaid, P. A. Towers, C. J. Scott, and K. A.S. Al-Shoumer Irregular cycles and steroid hormones in polycystic ovary syndrome Hum. Reprod., September 1, 2005; 20(9): 2402 - 2408. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Second World Congress on the Insulin Resistance Syndrome: Mediators, pediatric insulin resistance, the polycystic ovary syndrome, and malignancy Diabetes Care, July 1, 2005; 28(7): 1821 - 1830. [Full Text] [PDF]
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A. Gambineri, L. Patton, R. De Iasio, B. Cantelli, G. E. Cognini, M. Filicori, A. Barreca, E. Diamanti-Kandarakis, U. Pagotto, and R. Pasquali Efficacy of Octreotide-LAR in Dieting Women with Abdominal Obesity and Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3854 - 3862. [Abstract] [Full Text] [PDF]
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M.A. Checa, A. Requena, C. Salvador, R. Tur, J. Callejo, J.J. Espinos, F. Fabregues, J. Herrero, and (Reproductive Endocrinology Interest Group of the Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2005; 11(4): 375 - 390. [Abstract] [Full Text] [PDF]
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R. V. Mehta, K. S. Patel, M. S. Coffler, M. H. Dahan, R. Y. Yoo, J. S. Archer, P. J. Malcom, and R. J. Chang Luteinizing Hormone Secretion Is Not Influenced by Insulin Infusion in Women with Polycystic Ovary Syndrome Despite Improved Insulin Sensitivity during Pioglitazone Treatment J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2136 - 2141. [Abstract] [Full Text] [PDF]
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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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V. Jayagopal, E. S. Kilpatrick, S. Holding, P. E. Jennings, and S. L. Atkin Orlistat Is as Beneficial as Metformin in the Treatment of Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 729 - 733. [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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R. J. Norman Metformin--Comparison with Other Therapies in Ovulation Induction in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4797 - 4800. [Full Text] [PDF]
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 A. Gambineri, C. Pelusi, E. Manicardi, V. Vicennati, M. Cacciari, A. M. Morselli-Labate, U. Pagotto, and R. Pasquali Glucose Intolerance in a Large Cohort of Mediterranean Women With Polycystic Ovary Syndrome: Phenotype and Associated Factors Diabetes, September 1, 2004; 53(9): 2353 - 2358. [Abstract] [Full Text] [PDF]
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E. Vanky, K.A. Salvesen, R. Heimstad, K.J. Fougner, P. Romundstad, and S.M. Carlsen Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study Hum. Reprod., August 1, 2004; 19(8): 1734 - 1740. [Abstract] [Full Text] [PDF]
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L. J. Moran, M. Noakes, P. M. Clifton, G. A. Wittert, L. Tomlinson, C. Galletly, N. D. Luscombe, and R. J. Norman Ghrelin and Measures of Satiety Are Altered in Polycystic Ovary Syndrome But Not Differentially Affected by Diet Composition J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3337 - 3344. [Abstract] [Full Text] [PDF]
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R. J. Norman, M. Noakes, R. Wu, M. J. Davies, L. Moran, and J. X. Wang Improving reproductive performance in overweight/obese women with effective weight management Hum. Reprod. Update, May 1, 2004; 10(3): 267 - 280. [Abstract] [Full Text] [PDF]
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R. Homburg and C. B. Lambalk Polycystic ovary syndrome in adolescence--a therapeutic conundrum Hum. Reprod., May 1, 2004; 19(5): 1039 - 1042. [Abstract] [Full Text] [PDF]
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E. Vanky, K.A. Salvesen, and S.M. Carlsen Six-month treatment with low-dose dexamethasone further reduces androgen levels in PCOS women treated with diet and lifestyle advice, and metformin Hum. Reprod., March 1, 2004; 19(3): 529 - 533. [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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M. S. Coffler, K. Patel, M. H. Dahan, R. Y. Yoo, P. J. Malcom, and R. J. Chang Enhanced Granulosa Cell Responsiveness to Follicle-Stimulating Hormone during Insulin Infusion in Women with Polycystic Ovary Syndrome Treated with Pioglitazone J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5624 - 5631. [Abstract] [Full Text] [PDF]
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K. Patel, M. S. Coffler, M. H. Dahan, R. Y. Yoo, M. A. Lawson, P. J. Malcom, and R. J. Chang Increased Luteinizing Hormone Secretion in Women with Polycystic Ovary Syndrome Is Unaltered by Prolonged Insulin Infusion J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5456 - 5461. [Abstract] [Full Text] [PDF]
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 J. M Lord, I. H K Flight, and R. J Norman Metformin in polycystic ovary syndrome: systematic review and meta-analysis BMJ, October 25, 2003; 327(7421): 951. [Abstract] [Full Text] [PDF]
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 V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [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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U. Pagotto, A. Gambineri, C. Pelusi, S. Genghini, M. Cacciari, B. Otto, T. Castaneda, M. Tschop, and R. Pasquali Testosterone Replacement Therapy Restores Normal Ghrelin in Hypogonadal Men J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4139 - 4143. [Abstract] [Full Text] [PDF]
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P. G. Crosignani, M. Colombo, W. Vegetti, E. Somigliana, A. Gessati, and G. Ragni Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet Hum. Reprod., September 1, 2003; 18(9): 1928 - 1932. [Abstract] [Full Text] [PDF]
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L. Ibanez, K. Ong, A. Ferrer, R. Amin, D. Dunger, and F. de Zegher Low-Dose Flutamide-Metformin Therapy Reverses Insulin Resistance and Reduces Fat Mass in Nonobese Adolescents with Ovarian Hyperandrogenism J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2600 - 2606. [Abstract] [Full Text] [PDF]
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 A. S. M Ahmed Polycystic ovaries: the role of insulin Perspectives in Public Health, June 1, 2003; 123(2): 78 - 79. [PDF]
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 F. Zangeneh, Y. C. Kudva, and A. Basu Insulin Sensitizers Mayo Clin. Proc., April 1, 2003; 78(4): 471 - 479. [Abstract] [PDF]
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B. Schultes, K. M. Oltmanns, W. Kern, H. L. Fehm, J. Born, and A. Peters Modulation of Hunger by Plasma Glucose and Metformin J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1133 - 1141. [Abstract] [Full Text] [PDF]
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K. A. Virtanen, K. Hallsten, R. Parkkola, T. Janatuinen, F. Lonnqvist, T. Viljanen, T. Ronnemaa, J. Knuuti, R. Huupponen, P. Lonnroth, et al. Differential Effects of Rosiglitazone and Metformin on Adipose Tissue Distribution and Glucose Uptake in Type 2 Diabetic Subjects Diabetes, February 1, 2003; 52(2): 283 - 290. [Abstract] [Full Text] [PDF]
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L. Morin-Papunen, I. Vauhkonen, R. Koivunen, A. Ruokonen, H. Martikainen, and J. S. Tapanainen Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in the Treatment of Nonobese Women with Polycystic Ovary Syndrome: A Randomized Study J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 148 - 156. [Abstract] [Full Text] [PDF]
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U. Pagotto, A. Gambineri, V. Vicennati, M. L. Heiman, M. Tschop, and R. Pasquali Plasma Ghrelin, Obesity, and the Polycystic Ovary Syndrome: Correlation with Insulin Resistance and Androgen Levels J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5625 - 5629. [Abstract] [Full Text] [PDF]
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L. A. Stadtmauer, B. C. Wong, and S. Oehninger Should patients with polycystic ovary syndrome be treated with metformin?: Benefits of insulin sensitizing drugs in polycystic ovary syndrome--beyond ovulation induction Hum. Reprod., December 1, 2002; 17(12): 3016 - 3026. [Abstract] [Full Text] [PDF]
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 D. Kirpichnikov, S. I. McFarlane, and J. R. Sowers Metformin: An Update Ann Intern Med, July 2, 2002; 137(1): 25 - 33. [Abstract] [Full Text] [PDF]
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K. Elter, G. Imir, and F. Durmusoglu 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., July 1, 2002; 17(7): 1729 - 1737. [Abstract] [Full Text] [PDF]
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 L. S. Hermann and N. Wiernsperger Impaired glucose tolerance and metformin: clinical and mechanistic aspects The British Journal of Diabetes & Vascular Disease, May 1, 2002; 2(3): 177 - 183. [Abstract] [PDF]
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S. A. Arslanian, V. Lewy, K. Danadian, and R. Saad Metformin Therapy in Obese Adolescents with Polycystic Ovary Syndrome and Impaired Glucose Tolerance: Amelioration of Exaggerated Adrenal Response to Adrenocorticotropin with Reduction of Insulinemia/Insulin Resistance J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1555 - 1559. [Abstract] [Full Text] [PDF]
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R. Homburg Should patients with polycystic ovarian syndrome be treated with metformin?: A note of cautious optimism Hum. Reprod., April 1, 2002; 17(4): 853 - 856. [Abstract] [Full Text] [PDF]
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 S. Z. Yanovski and J. A. Yanovski Obesity N. Engl. J. Med., February 21, 2002; 346(8): 591 - 602. [Full Text] [PDF]
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 R. T. Chlebowski, E. Aiello, and A. McTiernan Weight Loss in Breast Cancer Patient Management J. Clin. Oncol., February 15, 2002; 20(4): 1128 - 1143. [Abstract] [Full Text] [PDF]
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R. M. Koivunen, L. C. Morin-Papunen, A. Ruokonen, J. S. Tapanainen, and H. K. Martikainen Ovarian steroidogenic response to human chorionic gonadotrophin in obese women with polycystic ovary syndrome: effect of metformin Hum. Reprod., December 1, 2001; 16(12): 2546 - 2551. [Abstract] [Full Text] [PDF]
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 Tackling polycystic ovary syndrome DTB, January 1, 2001; 39(1): 1 - 5. [Abstract] [Full Text] [PDF]
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