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Original Studies |
Departments of Obstetrics and Gynecology (L.C.M.-P., R.M.K., H.K.M., J.S.T.) and Clinical Chemistry (A.R.), University Hospital of Oulu, FIN-90220 Oulu; and Department of Medicine (I.V.), University Hospital of Kuopio, FIN-70210 Kuopio, Finland
Address correspondence and requests for reprints to: Dr. J. S. Tapanainen, Department of Obstetrics and Gynecology, University Hospital of Oulu, Kajaaninitie 52 A, FIN-90220 Oulu, Finland. E-mail: juha.tapanainen{at}oulu.fi
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although metformin has been used, for decades, in the treatment of hyperglycemia in type 2 diabetic patients, the glucose-lowering mechanisms of metformin are still not fully clarified. Studies on the effect of metformin on insulin sensitivity in type 2 diabetic patients have been clearly controversial (6, 7, 8). On the other hand, other studies have shown that metformin exerts its glucose-lowering effect by suppressing the excessive rate of hepatic glucose production (9, 10). Furthermore, recent studies on type 2 diabetic patients have revealed that the antihyperglycemic effect of metformin might be primarily attributable to decreased release of free fatty acids from adipose tissue, i.e. decreased lipolysis (11, 12, 13). Nevertheless, recent studies have indicated that this drug improves metabolic abnormalities, e.g. hyperinsulinemia and insulin resistance, in women with PCOS (14, 15, 16, 17). Furthermore, metformin administration to women with PCOS has resulted in decreased androgen levels (18), as well as in an improvement in menstrual pattern and ovulatory function (19, 20, 21). Because opposite results have also been published (22, 23), it remains unclear whether metformin acts directly by way of a true improvement of insulin sensitivity or indirectly by way of a diminution of weight in obese PCOS subjects (24).
Oral contraceptive (OC) pills are commonly used in the treatment of menstrual disturbances and hyperandrogenism in women with PCOS, but one major area of concern with OC treatment in these patients is the risk of disturbed glucose tolerance (25, 26). OC pills induce impairment of glucose tolerance and elevate insulin levels in healthy women, but these effects depend largely on the dose of estrogen and dose and type of progestin (25, 26).
This study was designed to compare the antihyperglycemic drug metformin and the commonly used ethinyl estradiol-cyproterone acetate (CA) OC pill in the treatment of PCOS in obese women. Special attention was paid to the effects of these two forms of medication 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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Thirty-two obese [body mass index (BMI) > 27
kg/m2] women with PCOS were recruited from the
Reproductive Endocrine Unit at Oulu University Hospital (Table 1
).
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8 subcapsular
follicles of 3- to 8-mm diameter in 1 plane in 1 ovary and increased
stroma) and at least one of the following symptoms: oligomenorrhea or
amenorrhea [12 of 14 (12/14) in the Diane Nova group and 9/11 in the
metformin group]; clinical manifestations of hyperandrogenism, such as
a hirsutism score of more than 7, according to Ferriman and Gallway
(28) (6/14 in the Diane Nova group and 5/11 in the metformin group);
acne (1/14 in the Diane Nova group); and/or an elevated
serum testosterone (T) level (>2.7 nmol/L) (5/14 in the Diane Nova
group and 3/11 in the metformin 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. One subject (metformin) moved away and 1 (metformin) stopped for personal reasons. Three (2 in the metformin group and 1 in the Diane Nova group) were dropped because of manifest diabetes mellitus (DM) during the oral glucose tolerance test (OGTT) before treatment. Two women discontinued treatment after 2 months because of side effects (1 in the metformin group because of continuous nausea and diarrhea and 1 in the Diane Nova group because of headache and high blood pressure). Twenty-five obese women were treated for 3 months and 18 for 6 months.
The study was approved by the Ethics Committee of the University of Oulu, and informed written consent was obtained from each subject.
Protocol of the study
The subjects were randomized to either the metformin group or to the OC pill group [ethinyl estradiol (35 µg), CA (2 mg), Diane Nova, Schering AG; 21 days/month followed by a 7-day pill-free period]. The metformin dose was doubled after 3 months of treatment (metformin hydrochloride, Diformin, Leiras, Finland: 500 mg x 2 daily for 3 months, then 1000 mg x 2 for 3 months) to study the effects of different doses and to ensure the drug effect.
All subjects were evaluated 1–7 days after spontaneous, or progestin-induced (amenorrheic patients), or Diane Nova-induced menstruation before the treatment and at 3 and 6 months of the 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 (10 mg/day for 10 days), which has only negligible effect on insulin sensitivity. Furthermore, to assure minimal progestin effect, the examinations were performed at least 7 days after the last progestin pill.
Clinical parameters and ultrasonography.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 RT-X200, Milwaukee, WI, with a 6.5-MHz probe) was carried out to measure ovarian volumes and the number of follicles. Volume determinations were carried out using the formula for the volume of an ellipsoid: 0.523 x length x width x thickness (29).
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 new American Diabetes Association
criteria in 1997: DM: 0 min 6.1 and/or at 120 min 10
mmol/L; impaired glucose tolerance: 0 min < 6.1 and at 120 min
6.7–10.0 mmol/L; impaired fasting glycemia (IFG): 0 min 5.6
and < 6.1 and at 120 min <6.7; normal glucose tolerance: 0
min < 5.6 and at 120 min < 6.7 (30). 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] (31). 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)
(32). 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 (33), because its hepatic extraction, unlike
that of insulin, is negligible (34). The incremental insulin
(AUCins) and glucose (AUGgluc) areas under the
curve were calculated by the trapezoidal method. Fasting serum
C-peptide x 1000/fasting serum insulin molar ratio was calculated
as an index of the hepatic insulin extraction in the fasting state
(35).
Euglycemic hyperinsulinemic clamp.The euglycemic hyperinsulinemic clamp technique was used for assessment of insulin sensitivity (36). A priming dose of insulin infusion (Actrapid, 100 IU/mL; Novo Nordisk, Genstofe, Denmark) was administered during the initial 10 min to raise serum insulin acutely to the desired level, where it was maintained by continuous insulin infusion of 80 mU/m2 body surface area per min. Blood glucose was clamped at 5 mmol/L 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% during the last 60 min of the clamp 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 equivalent to whole-body glucose uptake, i.e. whole-body glucose disposal (M-value) (37). Blood samples for the assay of serum lactate, insulin, and free fatty acids (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 (38). 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 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 was used for calculation. Protein, glucose, and lipid oxidation were calculated according to Ferrannini (39). Protein oxidation was calculated on the basis of the urinary nonprotein nitrogen excretion rate (39). 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), 17-hydroxyprogesterone (17-OHP), 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 insulin-like growth factor-binding protein-1 (IGFBP-1) were determined by immunoenzymometric assay using commercial reagents (Medix Biochemica, Kauniainen, Finland), and concentrations of T by using an automated chemiluminescence system (Ciba-Corning, Inc. ACS-180, Medfield, MA). The free androgen index (FAI) was calculated according to the equation: (Tx100)/SHBG. Levels of blood glucose, and serum lactate and FFAs were determined by standard methods.
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-OHP, 4.0 and 5.6% for T, 4.0 and 4.3%t 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, 1.5 and 2.3% for blood glucose, 2.2 and 3.8% for lactate, and 3.8 and 5.5% for FFA.
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 Diane Nova 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 Diane Nova 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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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical parameters are shown in Table 1.
In the metformin group, the mean BMI of the subjects tended to decrease
(P = 0.09) and waist-to-hip ratio (WHR)
(P = 0.01) had decreased significantly at 6 months
(Table 1, Fig. 1).
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). Menstrual cyclicity improved in six of the eight subjects during metformin treatment. Although barrier contraception was recommended during metformin treatment, one patient conceived after 4 months of treatment and three later at 7, 9, and 10 months after the onset of metformin treatment.
Metabolic parameters
Metabolic parameters of the subjects are shown in Table 1 and
Figs. 2 and 3.
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Fasting glucose levels had decreased significantly at 3 months
(P = 0.04) and 6 months (P = 0.04) of
metformin treatment. The AUCgluc did not change
significantly in the metformin group [14.1 ± 0.9
(SE) before treatment vs. 14.2 ±
1.1, P = 0.8 at 3 months; and 13.6 ± 1.4
mmol/L·h, P = 0.7 at 6 months], but it was increased
significantly at 6 months of Diane Nova treatment (from 14.3 ±
0.9 to 16.3 ± 1.4 at 3 months, P = 0.09; and to
16.2 ± 1.3 mmol/L·h at 6 months, P = 0.03, Fig. 2).
In the metformin group, fasting insulin concentrations had decreased at
3 months (P = 0.02) and at 6 months (P
= 0.02, Table 1). The AUCins tended to decrease
in the metformin group [from 1204.5 ± 165.3
(SE) to 953.5 ± 162.3 at 3 months,
P = 0.07; and to 827.4 ± 180.3 pmol/L·h at 6
months, P = 0.07, Fig. 2], but it did not change in
the Diane Nova group (1742.9 ± 466.9 before treatment
vs. 1491.1 ± 289.4, P = 0.9 at 3
months; and 1392.7 ± 300.3 pmol/L·h P = 0.4 at
6 months, Fig. 2). No significant change was observed in the fasting
serum C-peptide concentrations during either treatment (Table 1).
Early-phase insulin secretion was decreased slightly, but not
significantly, at 6 months in the metformin group (P =
0.2); but early-phase C-peptide secretion did not change significantly
in either group. Hepatic insulin extraction in the fasting state was
slightly increased at 6 months in the metformin group
(P = 0.2) but did not change in the Diane Nova group
(Table 1, P = 0.7).
The M-value increased slightly, but not significantly, during metformin
treatment [from 32.8 ± 3.1 (SE) to 32.3 ± 2.8,
P = 0.7 at 3 months; and to 35.9 ± 5.0
µmol/kg·min, P = 0.2, at 6 months], and it did not
change in the Diane Nova group (27.6 ± 3.1 before treatment
vs. 30.2 ± 4.1, P = 0.6, at 3 months;
and 25.6 ± 4.2 µmol/kg·min, P = 0.6, at 6
months, Fig. 3). In the metformin group, the rates of fasting glucose
oxidation increased (from 2.3 ± 0.8 to 6.7 ± 1.6 at 3
months, P = 0.06; and to 7.1 ± 1.0
µmol/kg·min at 6 months, P = 0.01, Table 1), and
the rates of glucose oxidation during the clamp (insulin-mediated) were
increased slightly at 3 months (P = 0.06) and
significantly at 6 months (P = 0.01) in the metformin
group (Fig. 3).
Energy expenditure, lipid oxidation, and serum FFA levels
The results are shown in Table 2.
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Endocrine parameters
The endocrine parameters are shown in Table 3.
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Serum concentrations of IGFBP-1 were increased in the Diane Nova group at 6 months (P = 0.03).
Serum A concentrations decreased significantly in both groups; serum concentrations of DHEA in the metformin group and those of DHEAS and 17-OHP in the Diane Nova group decreased significantly during the therapy.
In the Diane Nova group, serum leptin levels were increased significantly (P = 0.002) at 6 months of treatment, and serum fasting cortisol concentrations were increased at 3 and 6 months (P < 0.001).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mechanisms by which metformin improves hyperinsulinemia in PCOS subjects are of particular interest. A decrease in insulin secretion by the ß-cells is unlikely, because metformin has no direct effect on insulin secretion (40). Likewise, in our study, metformin had no effect on either basal or early-phase insulin secretion, estimated by C-peptide responses. On the other hand, we observed a trend towards an improvement in hepatic insulin extraction after 6 months of metformin therapy (P = 0.2), which was, however, unlikely alone to explain the improvement in hyperinsulinemia. Furthermore, although we observed significant improvement in the rates of glucose oxidation both in the fasting state and during the hyperinsulinemic clamp, whole-body glucose uptake (measuring peripheral insulin sensitivity) during the clamp did not improve significantly during metformin therapy (P = 0.2). Our results suggest that metformin could result in subtle improvements in both hepatic insulin extraction and insulin sensitivity in PCOS subjects, which together could lead to a significant decrease in hyperinsulinemia.
In many features of metabolic syndrome (41), such as in abdominal obesity (42) and type 2 diabetes (43), serum FFA concentrations are increased. It is well recognized that FFAs have a stimulatory effect on hepatic gluconeogenesis, which may lead to increased hepatic glucose output (44). Furthermore, FFAs compete with glucose for oxidation in skeletal muscle, according to Randle’s hypothesis (45). Therefore, elevated serum FFA concentrations may impair glucose disposal in skeletal muscle, and lead to impaired insulin sensitivity as a secondary event (42, 46, 47). Our study is the first in which the effect of metformin therapy on serum FFAs, the rates of lipid oxidation, and glucose utilization in PCOS subjects has been examined in some detail. Interestingly, we observed a significant decrease in both serum FFA concentrations and the rates of lipid oxidation in the fasting state and during hyperinsulinemic clamp, with concomitant improvement of oxidative utilization of glucose and reduction of hyperinsulinemia. Furthermore, the subtle improvement in hepatic insulin extraction observed in the present study might have been mediated by the inhibitory effect of metformin on FFAs, in line with the results of previous studies showing that elevation of serum FFA concentrations impairs hepatic insulin extraction (48). These results strongly suggest that the primary mechanism of metformin in improving hyperinsulinemia in PCOS subjects is mediated through decreased release of free FFAs from adipose tissue, in line with results of recent studies in type 2 diabetes patients (12, 13). Furthermore, in the present study, abdominal obesity decreased significantly in the metformin group. Whether the observed decrease in abdominal obesity in the present study was attributable to improved oxidative glucose utilization or whether it was the cause of decreased serum FFA concentrations after some unknown weight-lowering effect of metformin (40, 49) cannot be solved in this study.
The effects of metformin therapy on insulin sensitivity in PCOS
subjects have been controversial. Some investigators, assessing insulin
sensitivity by way of iv insulin tolerance tests (50) or the euglycemic
clamp technique (16, 17), have shown significant improvement of insulin
sensitivity during metformin treatment, whereas others have failed to
confirm it (22, 23, 24). It is likely that insulin resistance in obese PCOS
subjects is caused by both a primary defect in skeletal muscle and by
FFA-glucose competition (42, 51). The antilipolytic effect,
i.e. suppression of FFA release from adipose tissue, is
achieved at markedly lower insulin levels than is the stimulation
of glucose uptake in the skeletal muscle (52). Consequently, the effect
of metformin in improving glucose utilization can be better observed at
lower insulin concentrations than those observed during the
hyperinsulinemic clamp (12, 13). We observed a trend towards an
improvement in whole-body glucose uptake only at supraphysiological
serum insulin levels (
960 pmol/L) during the clamp. This strongly
suggests that the effect of metformin in improving glucose utilization
in our study subjects was, indeed, mainly mediated through its effect
on adipose tissue. However, recent studies, using a euglycemic
hyperinsulinemic clamp, showed a significant improvement of insulin
sensitivity at high supraphysiological insulin levels (1500 pmol/L),
suggesting that metformin may also have some direct insulin
sensitivity-improving effect in skeletal muscle (16, 17). The reason
for these discrepant results remains unclear, but they could, at least
partly, be attributable to heterogeneity of PCOS.
Menstrual cyclicity improved in more than half of the subjects during metformin treatment, and four of them conceived between 4 and 12 months of therapy. On the other hand, some subjects did not benefit from metformin therapy. It is tempting to speculate whether certain features of the patients could predict a beneficial response to metformin therapy. The results of a recent study have shown that responders had higher plasma insulin levels, lower serum A concentrations, and less severe menstrual abnormalities than nonresponders (17). In the present study, responders tended to be more obese and hyperandrogenic than nonresponders, but no significant difference was observed in insulin sensitivity or carbohydrate tolerance between these two groups. Because most of the effects of metformin became significant after increasing the dose to 2 g/day, this dosage seems to be required to obtain a sufficient effect.
In accordance with the results of some studies on metformin (16), but not with all (23), the circulating concentrations of T and some of the adrenal steroids decreased significantly during metformin therapy. However, because of a decrease in SHBG concentrations during therapy, the FAI did not change. This fact could explain why, despite the significant improvement in hyperandrogenism, the hirsutism scores did not improve during metformin therapy, as also observed in our previous study (20). In contrast, during Diane Nova treatment, SHBG increased and the FAI decreased significantly, and this treatment was very effective in improving hyperandrogenism symptoms such as hirsutism.
In the present study, we observed a significant worsening of glucose tolerance during Diane Nova treatment. Previous investigators have shown increased glucose and insulin responses during OGTTs in women taking combination OCs, but this increase has varied according to the type and dose of progestin (25, 26). Furthermore, evaluation of the effect of OCs on insulin sensitivity, using the euglycemic hyperinsulinemic clamp technique, has shown a significant decrease in insulin sensitivity during 3–6 months of treatment (53, 54). The results of studies involving CA have been controversial. One study, using the euglycemic clamp in PCOS women treated with Diane Nova, showed a significant decrease in insulin sensitivity (55); but in other studies, either no effects on circulating insulin concentrations and insulin resistance (56), or impairment of carbohydrate metabolism (57), have been observed, in line with the present results. Thus, despite its favorable effects on hirsutism, Diane Nova should be used with caution in obese PCOS women, especially in those subjects with a familial disposition to type 2 DM.
In conclusion, our results suggest that metformin, by way of its effect on adipose tissue, could lead to reduction of hyperinsulinemia and concomitant improvement of ovarian cyclicity and fertility. Because metformin has also been shown to improve the efficiency of ovulation induction treatments (21, 58), it could be a good alternative in the treatment of obese PCOS women who wish to become pregnant. Furthermore, because of its beneficial effects on fat metabolism, metformin might be useful in reducing the risk of cardiovascular diseases in PCOS subjects. Diane Nova, although slightly worsening glucose tolerance, is effective in the treatment of hyperandrogenic symptoms associated with PCOS.
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Acknowledgments |
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Footnotes |
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Received March 13, 2000.
Revised May 22, 2000.
Accepted June 5, 2000.
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References |
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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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 C. Honer, K. Nam, C. Fink, P. Marshall, G. Ksander, R. E. Chatelain, W. Cornell, R. Steele, R. Schweitzer, and C. Schumacher Glucocorticoid Receptor Antagonism by Cyproterone Acetate and RU486 Mol. Pharmacol., May 1, 2003; 63(5): 1012 - 1020. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC Diabetes Care, April 1, 2003; 26(4): 1297 - 1303. [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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L. Ibanez and F. de Zegher Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome Hum. Reprod., January 1, 2003; 18(1): 57 - 60. [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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J. E. Nestler Should patients with polycystic ovarian syndrome be treated with metformin?: An enthusiastic endorsement Hum. Reprod., August 1, 2002; 17(8): 1950 - 1953. [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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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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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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The ESHRE Capri Workshop Group Ovarian and endometrial function during hormonal contraception Hum. Reprod., July 1, 2001; 16(7): 1527 - 1535. [Abstract] [Full Text] [PDF]
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) and at 6 months (•) of metformin and Diane
Nova treatment. *, P < 0.1; **,
P < 0.05; ***, P < 0.01,
compared with the level before treatment.